US5776944A - 7-(4-aminomethyl-3-methyloxyiminopyrroplidin-1-yl)-1-cyclopropyl-6-flu oro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid and the process for the preparation thereof - Google Patents
7-(4-aminomethyl-3-methyloxyiminopyrroplidin-1-yl)-1-cyclopropyl-6-flu oro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid and the process for the preparation thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- the present invention relates to a novel quinoline(naphthyridine) carboxylic acid derivative having an excellent antibacterial activity. More specifically, the present invention relates to a novel quinoline(naphthyridine)carboxylic acid derivative represented by the following formula (I), which has an 4-aminomethyl-3-oximepyrrolidine substituent on 7-position of the quinolone nucleus and shows a superior antibacterial activity in contrast to the known quinolone antibacterial agents and also has a broad antibacterial spectrum and a highly improved pharmacokinetic property: ##STR2## and its pharmaceutically acceptable non-toxic salt, its physiologically hydrolyzable ester, solvate and isomer, in which
- R represents hydrogen, methyl or amino
- Q represents C--H, C--F, C--Cl, C--OH, C--CH 3 , C--O--CH 3 or N;
- R 1 represents cyclopropyl, ethyl, or phenyl which is substituted with one or more fluorine atom(s);
- R 2 represents one of the following a) through e):
- R 3 and R 4 independently of one another represent hydrogen or C 1 -C 3 alkyl or R 3 and R 4 together with a nitrogen atom to which they are attached can form a ring.
- the present invention also relates to a process for preparing the compound of formula (I), as defined above, and an antibacterial composition comprising the compound of formula (I) as an active component.
- nalidixic acid was first introduced as an agent for treating urinary tract infection (see, G. Y. Lesher, et al., J. Med. Chem. 5, 1063-1065 (1962)), numerous quinoline carboxylic acid antibacterial agents, including oxolinic acid, rosoxacin, pipemidic acid, etc., have been developed. However, these early-stage antibaterial agents have a little activity against gram-positive bacterial strains and thus have been used only against gram-negative strains.
- norfloxacin which is the quinolone compound having a fluorine on 6-position has been newly developed (see, H. Koga, et al., J. Med. Chem., 23, 1358-1363 (1980)), and thereafter an extensive study to develop various quinolone antibacterial compounds has been conducted.
- norfloxacin since norfloxacin has a weak antibacterial activity against gram-positive strains and shows poor distribution and absorption in living body, it has been used only for treatment of diseases including urinary tract infections, gastro-intestinal infections, sexually transmitted diseases and the like. Thereafter, ciprofloxacin (see, R. Wise, et al., J. Antimicrob.
- the compounds in use or under clinical test include mainly the derivatives having a piperazine substituent on 7-position of the quinolone nucleus as in ciprofloxacin or ofloxacin.
- a compound having an 3-amino or 3-aminomethylpyrrolidine group introduced into 7-position has an increased activity against gram-positive strains, in comparison with the compounds having 7-piperazine group, while maintaining a potent activity against gram-negative strains.
- the compounds having pyrrolidine substituent have a low solubility in water in comparison with the compounds having piperazine substituent, and thus their in-vivo antibacterial activity is not so high as the in-vitro activity. Accordingly, numerous study has been continuously conducted to improve the disadvantage of the compounds having pyrrolidine substituent, that is, to increase the solubility in water and to improve the pharmacokinetic property.
- R' represents hydrogen or methyl
- X represents C--H, C--F or N
- n denotes 1 or 2.
- the compound A! has some disadvantages that it shows a good antibacterial activity against gram-positive strains but a relatively weak activity against gram-negative strains, and also has a relatively low antibacterial activity in in-vivo test.
- Japanese Laid-open Patent Publication No. (Hei) 01-100165 (1989) discloses the compound having the following general formula B!: ##STR8## in which R represents cyclopropyl, 2,4-difluorophenyl or 4-hydroxy-phenyl;
- X represents C--H, C--F or C--Cl
- R' represents oxime or hydroxyaminopyrrolidine-derived substituent.
- European Early Patent Publication No. 0 541 086 discloses the quinolone compound having the following general formula C!: ##STR10## in which R and R 1 independently of one another represent hydrogen or C 1 -C 5 alkyl;
- R 2 represents hydrogen, amino, fluoro or hydroxy
- R 3 represents C 3 -C 7 cycloalkyl
- R 4 represents methoxy or fluoro
- R 5 and R 6 can be identical with or different from each other and independently of one another represent hydrogen or alkyl, or
- R 5 and R 6 together can form C 3 -C 5 cycloalkyl
- n denotes 0 or 1
- n denotes an integer of 1 to 3.
- the compound of formula C! does not include any compound having both oxime group and aminomethyl group on 7-position, and therefore, is different from the compound of the present invention.
- the common characteristic feature of the known oxime or hydroxyamine-derived compounds as mentioned above is that they exhibit a good activity against gram-positive strains including MRSA (Methicillin Resistant Staphylococcus aureus) strains in comparison with the early developed quinolone compounds but show a weak activity against gram-negative strains in comparison with the antibacterial agents including ofloxacin or ciprofloxacin. Therefore, it can be said that their antibacterial spectrum may be narrower than that of the known ofloxacin or ciprofloxacin antibacterial compound.
- MRSA Metal Resistant Staphylococcus aureus
- the present inventors have extensively studied to develop the novel oxime-aminomethyl compound, which shows a potent antibacterial activity against broad spectrum pathogenic strains including resistant strains and also exhibits more improved pharmacokinetic properties and high absorption in living body, by introducing various substituted pyrrolidine groups into 7-position of quinoline nucleus and determining pharmacological activities of the resulting compounds.
- the quinolone compounds having the general formula (I), as defined above, wherein 4-aminomethyl-3-(optionally substituted)oxime-pyrrolidine group is introduced into 7-position of quinoline nucleus can satisfy such purpose, and thus completed the present invention.
- It is a further object of the present invention to provide an antibacterial composition comprising the novel quinoline (naphthyridine)carboxylic acid derivative of formula (I) as an active component.
- FIG. 1 represents the moisture adsorption velocity profile of 7-(4-aminomethyl-3-methyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid methanesulfonate at 25° C.;
- FIG. 2 represents the isothermal moisture adsorption profile of 7-(4-aminomethyl-3-methyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid methanesulfonate at 25° C.;
- FIG. 3 represents the equilibrium moisture content of 7-(4-aminomethyl-3-methyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid methanesulfonate ⁇ 3 hydrate at a relative humidity of 23 to 75%;
- FIG. 4 represents test result on moisture adsorption of 7-(4-aminomethyl-3-methyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid methanesulfonate ⁇ 1.5 hydrate;
- FIG. 5 represents the powder X-ray diffraction pattern of 7-(4-aminomethyl-3-methyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid methanesulfonate anhydride;
- FIG. 6 represents the powder X-ray diffraction pattern of 7-(4-aminomethyl-3-methyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid methanesulfonate ⁇ 3 hydrate;
- FIG. 7 represents the powder X-ray diffraction pattern of 7-(4-aminomethyl-3-methyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid methanesulfonate ⁇ 1.5 hydrate;
- FIG. 8 represents the variation in moisture content with elapsed time of 7-(4-aminomethyl-3-methyloxyiminopyrrolidin-1-yl)-1-cyclocropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid methanesulfonate anhydride taken after 0, 5, 10, 20, 30, and 60 minutes, respectively, from the initial point while being passed through with humidified nitrogen;
- FIG. 9 represents the results of Differential Scanning Calorimetry on 7-(4-aminomethyl-3-methyloxylminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid methanesulfonate anhydride and 3 hydrate;
- FIG. 10 represents the results of thermogravimetric analysis on 7-(4-aminomethyl-3-methyloxylminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-l,4-dihydro-1,8-naphthyridine-3-carboxylic acid methanesulfonate ⁇ 3 hydrate.
- the present invention relates to a novel quinoline(naphthyridine) carboxylic acid derivative having the following formula (I): ##STR12## and its pharmaceutically acceptable non-toxic salt, its physiologically hydrolyzable ester, solvate and isomer, in which
- R represents hydrogen, methyl or amino
- Q represents C--H, C--F, C--Cl, C--OH, C--CH 3 , C--O--CH 3 or N;
- R 1 represents cyclopropyl, ethyl, or phenyl which is substituted with one or more fluorine atom(s);
- R 2 represents one of the following a) through e):
- R 3 and R 4 independently of one another represent hydrogen or C 1 -C 3 alkyl or R 3 and R 4 together with a nitrogen atom to which they are attached can form a ring.
- the preferred compounds include those wherein Q represents C--H, C--F, C--Cl, C-OMe or N, R represents hydrogen or amino, R 1 represents cyclopropyl or 2,4-difluorophenyl, R 2 represents hydrogen, methyl, ethyl, isopropyl, t-butyl, phenyl, propargyl, homopropargyl, 2-fluoroethyl, benzyl, 2-fluorobenzyl or 2-cyanobenzyl, and R 3 and R 4 represent hydrogen.
- More preferred compounds of formula (I) include those wherein Q represents C--H, C--Cl, C--F or N, R represents hydrogen or amino, R 1 represents cyclopropyl, R 2 represents methyl, t-butyl, homopropargyl, 2-fluoroethyl, henzyl or 2-fluorobenzyl, and R 3 and R 4 represent hydrogen.
- the 4-carbon atom on which aminomethyl group is substituted is an asymmetric carbon atom and thus can be present in the form of R or S or a mixture of R abd S.
- the compound of formula (I) can be present in the form of syn- and anti-isomers depending on their geometric structure.
- the present invention also includes all of those geometric isomers and their mixtures.
- the compound of formula (I) according to the present invention can form a pharmaceutically acceptable non-toxic salt.
- Such salt includes a salt with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, etc., a salt with organic carboxylic acids such as acetic acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid or malic acid or with sulfonic acids such as methanesulfonic acid, para-toluenesulfonic acid, etc., and a salt with other acids which are generally known and conventionally used in the technical field of quinolone-based compounds.
- These acid-addition salts can be prepared according to a conventional conversion method.
- the present invention relates to the 7-(4-aminomethyl-3-methyloxylminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid methanesulfonate and its hydrate represented by the following formula (H), ##STR17## in which n denotes 0, 1, 1.5, 2, 2.5, 3, 3.5 or 4, having an improved bioavailability.
- the methanesulfonate and its hydrate as defined above exhibit the same potent antibacterial activity as the free form, also have desirable physicochemical properties such as excellent solubility, constant moisture content, etc. regardless of the ambient relative humidity.
- a pseudopolymorph differs from the original compound not in its chemical properties, such as pharmacological activity, but in its physical properties, such as crystallinity, hygroscopicity, melting point, solubility, solubilizing velocity, etc. So, the pseudopolymorph has been recognized as pharmaceutically important (see, Morris, K. P. et al., Int. J. Pharm., 108, 15-206 (1994)).
- the salt In the process of identifying the physicochemical properties of methanesulfonate, the salt has been found to exist as a stable hydrate when the number of water molecules contained in one molecule varies within a specific range.
- stability does not mean chemical stability but the difficulty of removing water molecules. That is, a stable hydrate neither loses the water molecules contained therein nor absorbs moisture over a wide range of ambient relative humidity. In contrast, moisture absorption by the anhydride varies greatly with the ambient relative humidity.
- the moisture content of the hydrate varies with the hydration number (n) of the hydrated molecule. Since the molecular weight of 7-(4-amino-methyl-3-methyloxylminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid methanesulfonate is 485.5, the moisture content of the hydrate for n equal to 1, 1.5, 2, 2.5, 3, 3.5 or 4 is calculated to be 3.6%, 5%, 6.9%, 8.5%, 10.0%, 11.5% or 12.9%, respectively. However, the actual moisture content may differ from the calculated moisture content depending on differences in recrystallization conditions, drying conditions, etc. The range of the actual moisture content for each hydration number is shown in the following Table A.
- mixtures having a new moisture content by weight for example, a mixture of 1 hydrate and 1.5 hydrate having a moisture content of 2 to 6%; a mixture of 1.5 hydrate and 2 hydrate having a moisture content of 4 to 8%; a mixture of 2 and hydrate and 2.5 hydrate having a moisture content of 6 to 9%; a mixture of 2.5 hydrate and 3 hydrate having a moisture content of 8 to 11%; a mixture of 3 hydrate and 3.5 hydrate having a moisture content of 9 to 12%; or a mixture of 3.5 hydrate and 4 hydrate having a moisture content of 11 to 13%, can be obtained.
- the present invention also relates to a process for preparing the novel compound of formula (I).
- the compound of formula (I) can be prepared by reacting a compound of formula (II) with a compound of formula (III) or a salt thereof, as shown in the following reaction scheme 1.
- reaction scheme 1 ##STR18##
- R, R 1 , R 2 , R 3 , R 4 and Q are defined as previously described;
- X represents a halogen atom, preferably chlorine, bromine or fluorine.
- the compound of formula (I) according to the present invention can be prepared by stirring the compound of formula (II) and the compound of formula (III) in the presence of a solvent for 1 to 20 hours at the temperature between room temperature and 200° C. with the addition of a suitable base.
- the compound of formula (III) can be used in the form of a free compound or a salt with an acid such as hydrochloric acid, hydrobromic acid or trifluoroacetic acid.
- any solvent which does not adversely affect the reaction can be used.
- acetonitrile, dimethylformamide (DMF), dimethylsulfoxide (DMSO) pyridine, hexamethylphosphoramide (HMPA), N-methylpyrrolidinone, ethanol, and aqueous mixtures thereof can be used.
- This reaction is generally conducted in the presence of an acid acceptor.
- the reactant (III) is used in an excessive amount, for example, an equimolar amount to 10 times molar amount, preferably an equimolar amount to 5 times molar amount, with respect to the starting material (II).
- an equimolar amount to 10 times molar amount for example, an equimolar amount to 10 times molar amount, preferably an equimolar amount to 5 times molar amount, with respect to the starting material (II).
- the acid acceptor which can be preferably used in this reaction includes inorganic bases such as sodium hydrogen carbonate, potassium carbonate, etc., and organic bases such as triethylamine, diisopropylethylamine, pyridine, N,N-dimethylaniline, N,N-dimethylaminopyridine, 1,8-diazabicyclo 5.4.0! undec-7-ene(DBU), 1,4-diazabicyclo 2.2.2! octane(DABCO), etc.
- inorganic bases such as sodium hydrogen carbonate, potassium carbonate, etc.
- organic bases such as triethylamine, diisopropylethylamine, pyridine, N,N-dimethylaniline, N,N-dimethylaminopyridine, 1,8-diazabicyclo 5.4.0! undec-7-ene(DBU), 1,4-diazabicyclo 2.2.2! octane(DABCO), etc.
- the compound of formula (I) according to the present invention can also prepared by a method depicted in the following reaction scheme 2, in which a protecing group P is introduced into one of R 3 and R 4 of the compound of formula (III) wherein R 3 and R 4 are hydrogen to prepare the compound of formula (III') wherein the amino group is protected with P, the protected compound of formula (III') is reacted with the compound of formula (II) under the same condition as in the reaction scheme 1, and then the resulting compound of formula (I') is deprotected by removing the protecting group P to form the desired compound of formula (I).
- reaction scheme 2 In the above reaction scheme, R, R 1 , R 2 and Q are defined as previously described; and
- P represents an amino-protecting group.
- the compound of formula (III') can be used in the form of a free compound or a salt with hydrochloric acid, hydrobromic acid or trifluoroacetic acid, as in the compound of formula (III) used in the reaction scheme 1.
- protecting group P in the compound of formula (III') Any protecting group which is conventionally used in the field of organic chemistry and can be readily removed after the reaction without decomposition of the structure of the desired compound can be used as the suitable amino-protecting group P in the compound of formula (III').
- the specific example of protecting groups which can be used for this purpose includes formyl, acetyl, trifluoroacetyl, benzoyl, para-toluenesulfonyl, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl, para-methoxybenzyloxycarbonyl, trichloroethoxycarbonyl, beta-iodoethoxycarbonyl, benzyl, para-methoxybenzyl, trityl, tetrahydropyranyl, para-nitrobenzoyl, etc.
- the amino-protecting group present in the resulting compound of formula (I') can be removed by hydrolysis, solvolysis or reduction depending on properties of the relevant protecting group.
- the compound of formula (II) is treated in a solvent in the presence or absence of an acid or base at the temperature of 0° to 130° C. to remove the protecting group.
- an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.
- an organic acid such as acetic acid, trifluoroacetic acid, formic acid, toluenesulfonic acid, etc.
- a Lewis acid such as boron tribromide, aluminum chloride, etc.
- hydoxide of an alkali or alkaline earth metal such as sodium hydroxide, barium hydroxide, etc.
- an alkali metal carbonate such as sodium carbonate, calcium carbonate, etc.
- an alkali metal alkoxide such as sodium methoxide, sodium ethoxide, etc., or sodium acetate, and the like
- the reaction can be carried out in the presence of a solvent, for example, water or an organic solvent such as ethanol, tetrahydrofuran, dioxane, ethyleneglycol, acetic acid, etc., or a mixture of such organic solvent and water. If required, this reaction can also be practiced in the absence of any solvent.
- the protecting group is para-toluene-sulfonyl, benzyl, trityl, para-methoxybenzyl, benzyloxycarbonyl, para-methoxybenzyloxycarbonyl, trichloroethoxycarbonyl, betaiodoethoxycarbonyl and the like
- such groups can be effectively removed by means of a reduction.
- the reaction condition of the reduction for removing protecting group may be varied with properties of the relevant protecting group
- the reduction can be generally carried out with hydrogen gas stream in an inert solvent in the presence of a catalyst such as platinum, palladium, Raney nickel, etc., at the temperature of 10° to 100° C. or with metal sodium or metal lithium in ammonia at the temperature of -50° to -10° C.
- the compound of formula (II) used as the starting material in the present invention is a known compound and can be readily prepared according to a method known in the prior publication (see, J. M. Domagala, et al., J. Med. Chem. 34, 1142 (1991); J. M. Domagala, et al., J. Med. Chem. 31, 991 (1988); D. Bouzard, et al., J. Med. Chem. 35, 518 (1992)).
- the protecting groups P and P' independently of one another represent the same amino-protecting group as defined for P in connection with the compound of formula (III') and can be identical wraith or different from each other;
- a cyano ester 1! having a protected amino group can be reacted with sodium ethoxide in a solvent such as ethanol to obtain a 3-keto-4-cyanopyrrolidine 2!.
- the resulting cyanopyrrolidine 2! is reduced with hydrogen gas in the presence of a platinum catalyst to prepare an aminoalcohol 3!.
- the cyanopyrrolidine 2! may be reduced by means of other reductant to prepare the aminoalcohol 3!.
- the ketone and cyano groups can be reduced with lithium aluminumhydride(LAH), sodium borohydride-cobalt chloride complex(NaBH 4 --CoCl 3 ) or lithium borohydride(LiBH 4 ).
- the aminoalcohol 3! can be synthesized by reducing first the ketone group to a hydroxyl group by means of sodium borohydride(NaBH 4 ) and then reducing the cyano group by lithium aluminum hydride(LAH). Then, the amino group of the aminoalcohol 3! thus prepared is selectively protected to obtain a protected amine 4!, which is then treated with sulfur trioxide(SO 3 )-pyridine mixture in dimethylsulfoxide solvent (see, Parikh, J. R. and Doering, W. v. E. J. Am. Chem. Soc. 1967, 89, 5505), or oxidized with other oxidant, to prepare a ketone compound 5!. The resulting ketone compound 5!
- the ketone compound 5! is reacted with hydroxyamine to obtain the desired oxime compound 7! and the compound 7! is reacted with a suitable electrophilic compound of formula R 2 X which can introduce the desired R 2 group, in the presence of a base to prepare the oxime derivative of formula 6!, which is then deprotected by means of a suitable method selected depending on the kind of protecting group in the same manner as in the reaction scheme 3 to prepare the desired oxime compound (III-a).
- the amine compound 3! is treated with C 1 -C 3 aldehyde and then reduced to obtain a substituted amine compound 8! and the resulting amine compound 8! is treated with sulfur trioxide(SO 3 )-pyridine mixture in dimethylsulfoxide solvent, or oxidized with other oxidant, to obtain a ketone compound 9!.
- the resulting ketone compound 9! can be treated in the same manner as in the method for treating ketone compound 5! in the reaction schemes 3 and 4 to synthesize the desired compound of formula (III-b).
- the 7-(4-aminomethyl-3-methyloxylminopyrrolidin-1-yl) -1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid methanesulfonate can be prepared by adding the methanesulfonic acid to the corresponding quinolone carboxylic acid compound in an amount of 0.95 to 1.5 times molar amount with respect to the quinolone carboxylic acid compound, or by adding the same amount of the methanesulfonic acid which is already dissolved in a solvent to the quinolone carboxylic acid compound.
- solvents suitable for the above preparation include C 1 -C 4 haloalkanes, C 1 -C 8 alcohols and water, a solvent selected from the group consisting of dichloromethane, chloroform, 1,2-dichloroe- thane, methanol, ethanol, propanol, and water is preferred.
- the quinolone carboxylic acid compound in a solvent may be heated to dissolve the former before the methanesulfonic acid is added. If the quinolone carboxylic acid compoundsolution exists as a suspension, acid may be added to the suspension to obtain a thoroughly transparent solution.
- the resulting reaction mixture is stirred for 1 to 24 hours at a temperature of -10° to 40° C. or is allowed to stand, then the product is obtained as a solid according as the solubility of the product decreases.
- the methanesulfonate can also be obtained in a high yield by removing the solvent used under reduced pressure.
- the hydrates of the methanesulfonate of the present invention may easily be prepared by means of conventional methods well known in the art to which the present invention pertains. Particularly, the different hydrates may be prepared merely by changing recrystallization conditions.
- the present invention also provides an antibacterial composition
- an antibacterial composition comprising the novel compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof as an active component together with a pharmaceutically acceptable carrier.
- a pharmaceutically acceptable carrier which can be used for this purpose may be solid or liquid.
- the solid or semi-solid pharmaceutical preparation in the form of powders, tablets, dispersible powders, capsules, cachets, suppositories and ointments may be prepared in which case solid carriers are usually used.
- the solid carrier which can be used is preferably one or more substances selected from the group consisting of diluents, flavouring agents, solubilizing agents, lubricants, suspending agents, binders, swelling agents, etc. or may be encapsulating substances.
- the micronized active component is contained in an amount of 5 or 10 to 70% in the carrier.
- the suitable solid carrier includes magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectine, dextrin, starch, gelatin, tragaganth, methylcellulose, sodium carboxymethylcellulose, low boiling wax, cocoa butter, etc. Because of their ease in administration, tablets, powders, cachets and capsules represent the most advantageous solid preparation for oral administration.
- the liquid preparation includes solutions, suspensions and emulsions.
- the injectable preparation for parenteral administration may be in the form of water or waterpropyleneglycol solution, of which isotonicity, pH and the like can be adjusted to be suited for the physiological condition of living body.
- the liquid preparation can also be prepared in the form of a solution in aqueous polyethyleneglycol solution.
- the aqueous solution for oral administration can be prepared by dissolving the active component in water and adding a suitable coloring agent, flavouring agent, stabilizer and thickening agent thereto.
- the aqueous suspension suitable for oral administration can be prepared by dispersing the micronized active component in viscous substances such as natural or synthetic gum, methylcellulose, sodium carboxymethylcellulose and other known suspending agent.
- Dosage unit forms of the preparation refer to physically discrete units suitable as unitary dosage, each unit containing a predetermined quantity of the active component calculated to produce the desired therapeutic effect.
- Such dosage unit form can be in the packaged form, for example, a tablet, a capsule or a powder filled in vial or ampule, or an ointment, gel or cream filled in tube or bottle.
- the amount of the active component contained in the dosage unit form can be varied, it can be generally adjusted within the range of 1 to 100 mg depending on the efficacy of the selected active component.
- the active compound of formula (I) of the present invention When used as a medicine for treatment of bacterial infections, it is preferably administered in an amount of about 6 to 14 mg per kg of body weight at the first stage.
- the administration dosage can be varied with the requirement of the subject patient, severity of the infections to be treated, the selected compound and the like.
- the preferred dosage suitable for a certain condition can be determined by a person skilled in this art according to a conventional manner.
- the therapeutic treatment is started from the amount less than the optimal dosage of the active compound and then the administration dosage is increased little by little until the optimal therapeutic effect is obtained.
- the total daily dosage can be divided into several portions and administered over several times.
- the compound of the present invention shows a potent and broad spectrum antibacterial activity against various pathogenic organisms including gram-positive and gram-negative strains.
- the antibacterial activity of the present compound against gram-negative strains is comparable to or higher than that of the known antibacterial agents (for example, ciprofloxacin), and particularly, the antibacterial activity of the present compound against gram-positive strains is far superior to that of the known antibacterial agents.
- the present compound also exhibits a very potent antibacterial activity against the strains resistant to the known quinolone compounds.
- the compound of the present invention has a high water-solubility and thus can be well absorbed in the living body, in comparison with the known quinolone compounds, to show a very high bioavailability.
- the biological half life of the present compound is far longer than that of the known quinolone compounds, and therefore, the present compound can be administered once a day to be suitably used as an antibacterial agent.
- the compound according to the present invention is less toxic, it can be effectively used for prophylaxis and treatment of diseases caused by bacterial infections in warmblooded animals including human being.
- Boc represents t-butoxycarbonyl.
- the reaction was continuously conducted for further one hour under refluxing with heating.
- the reaction solution was concentrated under reduced pressure and the residue was diluted with water and then washed with methylene chloride.
- the aqueous layer was adjusted with 1N HCl to pH 4 and extracted with ethyl acetate.
- the extract was dried over anhydrous magnesium sulfate and then filtered.
- the filtrate was concentrated to obtain a stoichiometric amount of the title compound in a crude state.
- the resulting solid complex was dissolved in 4 L of ammonia water and this solution was diluted with 8 L of water and then extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and mixed with the mixture of 1.5 L of dioxane and 0.5 L of distilled water. 212 g of di-t-butoaycarbonyldicarbonate was added thereto and the whole mixture was stirred for 2 hours at room temperature. After the react ion is completed, the reaction mixture was concentrated under reduced pressure, diluted again with dichloromethane, washed with water, dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated and then purified with silica gel column chromatography (eluant: hexaneethyl acetate 2:1 by volume) to obtain 202 g (Yield: 64%) of the title compound.
- the resulting product was diluted with 200 of dioxane-water (2:1 by volume) and 12.3 g (0.056 mole) of di-t-butoxycarbonyldicarbonate was added portionwise thereto. The mixture was stirred for 30 minutes to complete the reaction, and then concentrated, diluted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated and the residue was purified with column chromatography to obtain 12.3 g (Yield: 83%) of the title compound.
- Example 1 The same starting material as Example 1 was reacted with each of the compounds prepared in Preparations 19 to 28 according to the same procedure as Example 1 to prepare the respective compounds listed in the following Table 8.
- Example 12 The same starting material as Example 12 was reacted with each of the compounds prepared in Preparations 19 to 28 according to the same procedure as Example 12 to prepare the respective compounds listed in the following Table 9.
- Example 23 The same starting material as Example 23 was reacted with each of the compounds prepared in Preparations 19 to 28 according to the same procedure as Example 23 to prepare the respective compounds listed in the following Table 10.
- Example 34 The same starting material as Example 34 was reacted with each of the compounds prepared in Preparations 19 to 28 according to the same procedure as Example 34 to prepare the respective compounds listed in the following Table 11.
- Example 45 The same starting material as Example 45 was reacted with each of the compounds prepared in Preparations 19 to 28 according to the same procedure as Example 45 to prepare the respective compounds listed in the following Table 12.
- Example 56 The same starting material as Example 56 was reacted with each of the compounds prepared in Preparations 19 to 28 according to the same procedure as Example 56 to prepare the respective compounds listed in the following Table 13.
- Example 67 The same starting material as Example 67 was reacted with each of the compounds prepared in Preparations 19 to 28 according to the same procedure as Example 67 to prepare the respective compounds listed in the following Table 14.
- Example 78 The same starting material as Example 78 was reacted with each of the compounds prepared in Preparations 19 to 28 according to the same procedure as Example 78 to prepare the respective compounds listed in the following Table 15.
- a sonicator filled with water was adjusted to 40° C. and was sealed with a lid. Then, a nitrogen introducing tube and a nitrogen excreting tube were connected to the vessel. When the pressure of the dried nitrogen introduced through the nitrogen introducing tube was adjusted to 20 psi, the relative humidity of the humidified nitrogen excreted through the excreting tube was more than 93%.
- 1 g of the anhydride having moisture content of about 2.5% prepared in Example 204 was introduced into a fritted filter and the humidified nitrogen prepared according to the above mentioned process was passed through. Samples were taken after 0, 5, 10, 20, 30, and 60 minutes, respectively, and the moisture content with the lapse of time was measured. From the results shown in FIG. 8, it can be seen that moisture content of about 10% is constantly maintained when the humidifying procedure is carried out over 30 minutes.
- the X-ray diffraction pattern of the humidified sample was identical to that the 3 hydrate obtained after recrystallization.
- the title compound can be prepared by two different processes.
- Example 204 1.0 g of the anhydride prepared in Example 204 was dissolved in 17 ml of a mixture of water and acetone (10/7, v/v). The solvent was slowly evaporated in darkness leaving 0.8 g of the title compound as a solid.
- Example 204 In the second process, 5.0 g of the anhydride prepared in Example 204 was added to 10 ml of water and the mixture was heated to about 45° C. in order to dissolve the anhydride. After 20 ml of ethanol was added thereto, the resulting solution was stirred and then allowed to stand to form a solid. The solid thus produced was filtered and dried under nitrogen flow to obtain 2.6 g of the title compound.
- the antibacterial activity of the compounds according to the present invention was determined by measuring their minimum inhibitory concentrations (MIC, ⁇ g/ml), against standard strains, clinically isolated strains and strains resistant to some antibacterial agents.
- the known antibacterial compounds, ofloxacin and ciprofloxacin were used as the comparative agents.
- the minimum inhibitory concentration could be determined by diluting the test compounds according to a two-times dilution method, dispersing the diluted test compounds in Mueller-Hinton agar medium and then inoculating 5 ⁇ l of the standard strain having 10 7 CFU per ml to the medium, which is then incubated for 18 hours at 37° C. The measured results are described in the following Table 25.
- the pharmacokinteic property parameters of the compounds of the present invention were determined using SD rats (male), weighing about 230 ⁇ 10 g. Specifically, the test compounds of the present invention were administered in an amount of 20 mg/kg of body weight to test rats via femoral veins. Then, bloods were collected at certain intervals after administration of the test compounds from femoral veins and analyzed by means of Agar Well Method to measure the blood concentration of the test compounds from which pharmacokinetic parameters, half life (T 1/2 ), and AUC (area under the curve), were calculated. The obtained results are described in the following Table 26.
- test solution containing the compounds in various concentrations were orally administered to ICR male mouse in an amount of 10 ml per kg of body weight.
- LD 50 value mg/kg
- the moisture adsorption velocity and the equilibrium moisture content of the anhydride prepared in Example 203 were determined by means of an automatic moisture adsorption analyzer (MB 300 G Gravimetric Sorption Analyzer). This instrument produces a specific relative humidity at a specific temperature and continuously records the weight change of a sample due to adsorption or desorption of moisture as measured by a micro balance inside the instrument. 16 mg of the anhydride sample was loaded on the micro balance and the moisture contained in the sample was removed under a dry nitrogen stream at 50° C. A weight change of less than 5 ⁇ g per 5 minutes was the criterion for complete dryness.
- FIG. 1 shows the moisture adsorption velocity, that is, the time required for the sample to reach equilibrium at each relative humidity from 0 to 95% at 5% intervals. Initial moisture adsorption proceeded very speedily at each relative humidity tested. In most cases, the equilibrium was reached within 2 hours.
- FIG. 2 shows the weight increment(%) at each relative humidity, that is, the equilibrium moisture content. It is clear from FIG. 2 that the equilibrium moisture content is dependent upon the relative humidity.
- METTLER TOLEDO DSC821e and METTLER TOLEDO STARe System were used for the Differential Scanning Calorimetry. 3.7 mg of sample was weighed into the aluminum pan, which was then press sealed with an aluminum lid. After three tiny needle holes were made on the lid, the sample was tested by heating from normal temperature to 250° C. at a rate of 10° C./min. As can be seen from FIG. 9, the endothermic peak due to the vaporization of the water molecules contained in the 3 hydrate begins at around 50° C. and the exothermic peak due to the thermal decomposition was observed at around 180° to 220° C. In contrast, the anhydride showed only an exothermic peak due to thermal decomposition at around 185° to 220° C. without any endothermic peak.
- thermogravimetric analysis SEIKO TG/DTA220 was used. 3.8 mg of the sample was weighed into an aluminum pan and was heated from normal temperature to 250° C. at a rate of 10° C./min according to the temperature raising program. As can be seen from FIG. 10, weight decrement was observed at the temperature range of endothermic peak, the extent of which corresponds to the moisture content determined by Karl-Fisher method (Mettler Toledo DL37KF Coulometer).
- Example 204 After 50 mg of the anhydride in Example 204, the 3 hydrate in Example 205, and the 1.5 hydrate in Example 206 were each thinly spread on the sample holder, X-ray diffraction analyses (35 kV ⁇ 20 mA Rigaku Gergeflex D/max-IIIC) were performed under the conditions listed below.
- the methanesulfonate shows a water solubility superior to that of the tartarate, the sulfurate, and the p-toluenesulfonate as well as the free form. Therefore, it is identified that the methanesulfonate has a desirable solubility as well as an excellent antibacterial activity.
- Example 204 In order to determine the antibacterial activitiers of the E- and Z-isomner of the compound 180 which were separated in Example 203, and of 7- (4-aminomethyl-3-methyloxylminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid methanesulfonate prepared in Example 204, in vitro antibacterial activities of them were measured using agar medium dilution method. The results were as described in the following Tables 31 and 32.
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Abstract
Description
TABLE A ______________________________________ Moisture Content according to Hydration Number Hydration Number (n) Moisture Content (%) ______________________________________ 1 2-4 1.5 4-6 2 6-8 2.5 8-9 3 9-11 3.5 11-12 4 12-13 ______________________________________
TABLE 1 __________________________________________________________________________Preparations 8 to 17 FAB Prep. R.sub.2 NMR (CDCl.sub.3), δ (ppm) MS (M + H) __________________________________________________________________________ 8 4-nitrobenzyl 8.2(2H, m), 7.4(2H, m), 5.2(2H, s), 4.9(1H, 465 s), 4.2(2H, m), 3.8(1H, m), 3.5-3.2(3H, m), 3.0(1H, m), 1.5(18H, s) 9 4-methoxybenzyl 7.3(2H, m), 6.9(2H, m), 5.0(2H, s), 4.9(1H, 450 s), 4.1(2H, m), 3.8(3H, s), 3.75(1H, m), 3.5-3.0(4H, m), 1.45(18H, s) 10 4-fluorobenzyl 7.3(2H, m), 7.0(2H, m), 5.0(2H, s), 4.8(1H, 438 br), 4.2(2H, m), 3.9(1H, m), 3.4(3H, m), 3.0(1H, m), 1.46(18H, s) 11 4-t-butylbenzyl 7.4-7.3(4H, m), 5.1(2H, s), 5.0(1H, s), 476 4.1(2H, m), 3.8(1H, m), 3.6-3.0(4H, m), 1.45(18H, s), 1.3(9H, s) 12 2-cyanobenzyl 7.8-7.3(4H, m), 5.3(2H, s), 5.0(1H, bs), 445 4.2(2H, s), 3.9(1H, m), 3.6-3.2(3H, m), 3.0(1H, s), 1.5(18H, s) 13 3-pyridylmethyl 8.6(2H, m), 7.7(1H, m), 7.3(1H, m), 5.1(2H, 421 s), 4.9(1H, s), 4.1(2H, m), 3.8(1H, m), 3.6-3.2(3H, m), 3.0(1H, m), 1.5(18H, s) 14 7.4(2H, m), 6.5(1H, m), 4.9(2H, s), 4.9(1H, s), 4.1(2H, m), 3.8(2H, m), 3.2(3H, m), 1.5(18H, s) 410 15 ##STR30## 7.7(2H, m), 7.2(1H, m), 5.5(1H, s), 5.0(1H, s), 4.2(2H, m), 3.8(1H, m), 3.6-3.1(4H, m), 1.5(18H, 495 16 ##STR31## 6.9(3H, m), 6.0(2H, m), 5.0(3H, m), 4.1(2H, m), 3.8(1H, m), 3.6-3.2(3H, m), 3.0(1H, m), 1.5(18H, 464 17 ##STR32## 7.3-7.0(3H, m), 6.8(1H, s), 5.1(1H, s), 4.2(2H, m), 3.8(1H, m), 3.5-3.0(4H, m), 1.6-1.4(27H, 496 __________________________________________________________________________
TABLE 2 __________________________________________________________________________ Preparations 19 to 28 FAB Prep. R.sub.2 NMR (CDCl.sub.3), δ (ppm) MS (M + H) __________________________________________________________________________ 19 4-nitrobenzyl 10.3-10.1(2H, s), 8.3(3H, s), 8.2(2H, d), 265 7.7(2H, d), 5.3(2H, s), 4.1(2H, m), 3.7(1H, m), 3.4(2H, m), 3.1(2H, m) 20 4-methoxybenzyl 10.2-10.0(2H, s), 8.4(3H, s), 7.3(2H, d), 250 6.9(2H, d), 5.0(2H, s), 3.9(2H, m), 3.73(3H, s), 3.7(1H, m), 3.4(2H, m), 3.1(2H, m) 21 4-fluorobenzyl 10.2(2H, s), 8.4(3H, s), 7.3(2H, m), 7.2(2H, 238 m), 5.1(2H, s), 3.9(2H, m), 3.7(1H, m), 3.4(2H, m), 3.1(2H, m) 22 4-t-butylbenzyl 10.2(2H, s), 8.4(3H, s), 7.4-7.3(4H, m), 276 5.1(2H, s), 3.9(2H, m), 3.7(1H, m), 3.2 (2H, m), 3.1(2H, m), 1.3(9H, s) 23 2-cyanobenzyl 10.2-10.0(2H, s), 8.2(3H, s), 7.9-7.5(4H, 245 m, 5.3(2H, s), 4.0(2H, m), 3.7(1H, m), 3.2(2H, m), 3.1(2H, m) 24 3-pyridylmethyl 10.3(1H, s), 10.1(1H, s), 8.9(1H, s), 8.8 221 (1H, m), 8.5(1H, d), 8.4(3H, m), 8.0(1H, m), 5.4(2H, s), 4.0(2H, m), 3.7(1H, m), 3.4 (2H, m), 3.1(2H, m) 25 10.3(2H, s), 8.4(3H, s), 7.6(1H, s), 6.4(1H, s), 5.0(2H, s), 4.0(2H, m), 3.8(1H, m), 3.4(2H, m), 3.1(2H, 210 26 ##STR35## 10.3(2H, s), 8.3(3H, s), 8.1(1H, m), 7.9 (1H, m), 7.4(1H, m), 5.5(2H, s), 4.1(2H, m), 3.9(1H, m), 3.14(2H, m), 3.1(2H, m) 295 27 ##STR36## 10.2(2H, s), 8.3(3H, s), 7.0(3H, m), 6.3 (2H, s), 5.3(2H, m), 4.1(2H, m), 3.9(1H, m), 3.4-3.2(2H, m), 3.1(2H, m) 264 28 ##STR37## 10.3-10.2(2H, s), 8.4(3H, s), 8.0-7.3(3H, m), 7.0(1H, s), 4.2(2H, m), 3.8(1H, m), 3.5-3.2(3H, m), 3.0(1H, 296 __________________________________________________________________________
TABLE 3 __________________________________________________________________________Preparations 31 to 36 FAB Prep. R.sub.2 .sup.1 H NMR (CDCl.sub.3), δ (ppm) MS (M + H) __________________________________________________________________________ 31 isopropyl 5.0(1H, br), 4.1(2H, s), 4.0(1H, m), 3.4 372 (1H, m), 3.55-3.25(3H, m), 3.0(1H, m), 1.55(18H, s), 1.0(6H, d) 32 cyclobutyl 4.7(1H, m), 4.2(2H, s), 3.8(1H, m), 3.4(1H, 384 m), 3.3(2H, m), 3.0(1H, m), 2.3(2H, m), 2.1 (2H, m), 1.8(1H, m), 1.6(1H, m), 1.5(18H, s) 33 cyclopentyl 4.7(1H, m), 4.1(2H, m), 3.7(1H, m), 398 3.4(1H, m), 3.3(2H, m), 3.0(1H, m), 1.8(4H, m), 1.7(4H, m), 1.6(18H, s) 34 5.0-4.8(1H, m), 4.3-3.7(6H, m), 3.3(2H, m), 3.0(1H, m), 2.1(2H, m), 1.5(18H, s), 1.3(2H, m) 400 35 cyclopropyl- 5.1(1H, br), 4.1(2H, m), 3.9(2H, m), 3.8(1H, 384 methyl m), 3.5(1H, m), 3.3(2H, m), 3.0(1H, m), 1.5 (18H, s), 1.1(1H, m), 0.6(2H, s), 0.3(2H, s) 36 isobutyl 5.05(1H, br), 4.15(2H, s), 4.1(2H, d), 386 3.6(2H, m), 3.3(1H, m), 3.0(2H, m), 2.5(1H, m), 1.5(18H, s), 1.05(6H, d) __________________________________________________________________________
TABLE 4 ______________________________________ Preparations 38 and 39 FAB Prep. R.sub.2 .sup.1 H NMR (CDCl.sub.3), δ (ppm) MS (M + H) ______________________________________ 38 methoxymethyl 5.15-4.9(3H), 4.15(2H, m), 3.75 374 (1H, m), 3.5-3.2(5H), 3.0(1H, m), 1.5(18H, s) 39 2-chloroethyl 4.9(1H, m), 4.30(2H, t), 4.1(2H, 392 s), 3.7(3H, m), 3.6(1H, m), 3.5- 3.0(3H, m), 1.45(18H, s) ______________________________________
TABLE 5 __________________________________________________________________________Preparations 41 to 50 FAB Prep. R.sub.2 .sup.1 H NMR (CDCl.sub.3), δ (ppm) MS (M + H) __________________________________________________________________________ 41 CH.sub.2 CH.sub.2 C CH 10.1-9.8(2H, br), 8.2(3H, br), 4.3(2H, t), 182 4.0(2H, s), 3.7(1H, m), 3.6-3.2(3H, m), 3.0(1H, m), 2.8(1H, s), 2.6(2H, t) 42 isopropyl 10.1-9.8(2H, br), 8.3(3H, br), 4.4(1H, m), 172 3.9(2H, d), 3.7(1H, m), 3.3(2H, s), 3.1(2H, m), 1.2(6H, d) 43 cyclobutyl 10.2-9.8(2H, br), 8.2(3H, br), 4.8(1H, m), 184 4.3(2H, s), 3.7(1H, m), 3.6-3.2(3H, m), 3.0(1H, m), 1.8(2H, m), 1.7(2H, m), 1.5(1H, m), 1.45(1H, m) 44 cyclopentyl 10.2-9.8(2H, br), 8.2(3H, br), 4.7(1H, m), 198 4.3(2H, s), 3.8(1H, m), 3.3(1H, m), 3.2(3H, m), 1.8(4H, m), 1.6(2H, m), 1.5(2H, m) 45 10.1-9.8(2H, br), 8.3(3H, s), 4.1-3.6 (10H, m), 3.2(2H, s), 2.2-1.9(2H, m) 200 46 cyclopropyl- 10.1-9.8(2H, br), 8.3(3H, s), 4.0-3.8 184 methyl (4H, m), 3.65(1H, m), 3.4(2H, m), 3.1(2H, m), 1.1(1H, m), 0.5(2H, d), 0.2(2H, d) 47 isobutyl 10.3-9.9(2H, br), 8.4(3H, br), 3.9-3.8 186 (4H, m), 3.65(1H, m), 3.3(2H, s), 3.1(2H, m), 1.9(1H, m), 0.85(6H, d) 48 propargyl 10.0(1H, m), 8.3(2H, m), 4.8(2H, s), 168 4.0(2H, m), 3.7(1H, m), 3.6(1H, s) 3.4(2H, m), 3.1(2H, s) 49 methoxymethyl 10-9.6(2H, br), 8.2(3H, br), 5.1(2H, dd) 174 4.1-3.8(2H, m), 3.7(1H, m), 3.3-3.0(4H, m) 50 2-chloroethyl 10-9.7(2H, br), 8.2(3H, br), 4.3(2H, t), 192 4.0(2H, m), 3.8(2H, t), 3.7(1H, m), 3.4(2H, m), 3.2(1H, m), 3.1(2H, m) __________________________________________________________________________
TABLE 6 ______________________________________Preparations 52 and 53 FAB Prep. R.sub.2 .sup.1 H NMR (CDCl.sub.3), δ (ppm) MS (M + H) ______________________________________ 52 phenyl 7.3(5H, m), 4.97(1H, bs), 3.8-2.8 406 (7H, m), 1.40(18H, s) 53 --CH.sub.2 CH.sub.3 5.0(1H, bs), 3.8-2.8(7H, m), 1.42 358 (18H, s), 1.41(18H, s), 1.38(3H, t) ______________________________________
TABLE 7 ______________________________________Preparations 55 to 57 FAB Prep. R.sub.2 .sup.1 H NMR (CDCl.sub.3), δ (ppm) MS (M + H) ______________________________________ 55 --H 4.1-3.2(7H, m) 130 56 Ph 7.2-7.4(5H, m), 4.1-3.2(7H, m) 206 57 --CH.sub.2 CH.sub.3 4.2-3.1(9H, m), 1.3(3H, t) 158 ______________________________________
TABLE 8 __________________________________________________________________________ Examples 2 to 11 ##STR50## FAB, Reac. Examp. NMR MS time Yield No. R .sup.1 H NMR, δ (ppm) solv. (M + 1) (min) (%) __________________________________________________________________________ ##STR51## 8.73(1H, s), 8.05(1H, d), 7.30 (2H, d), 6.98(2H, d), 5.10(2H, s), 4.61(2H, s), 4.25(1H, m), 3.90(1H, m), 3.80(3H, s), 3.70 (1H, m), 3.00(3H, m), 1.26(2H, m), 1.07(2H, m) CDCl.sub.3 496 10 75 3 ##STR52## 8.75(1H, s), 8.05(1H, d), 7.45 (2H, d), 7.30(2H, d), 5.15(2H, s), 4.62(2H, s), 4.25(1H, m), 3.85(1H, m), 3.75(1H, m), 3.10 (1H, m), 2.98(2H, m), 1.35(9H, s), 1.25(2H, m), 1.09(2H, m) CDCl.sub.3 522 15 76 4 ##STR53## 8.68(1H, s), 8.00(1H, d), 7.35 (2H, m), 7.10(2H, m), 5.08(2H, s), 4.59(2H, s), 4.20(1H, m), 3.95(1H, m), 3.81(1H, m), 3.00 (3H, m), 1.23(2H, m), CDCl.sub.3) 484 15 80 5 ##STR54## 8.59(1H, s), 8.21(2H, d), 8.06 (1H, s), 7.64(2H, d), 5.29(2H, s), 4.68(2H, s), 4.20(1H, m), 3.95(1H, m), 3.85(1H, m), 3.10 (1H, m), 2.80(2H, m), 1.18(2H, m), 1.10(2H, m) DMSO 511 10 76 6 ##STR55## 8.58(1H, s), 8.05(1H, d), 7.92- 7.42(4H, m), 5.28(2H, s), .65(2H, s), 4.20(1H, m), 3.95 (1H, m), 3.78(1H, m), 3.10(1H, m), 2.80(2H, m), 1.20(2H, m), 1.09(2H, DMSO 491 20 82 7 ##STR56## 8.74(1H, s), 8.10(1H, d), 6.92 (3H, m), 6.10(2H, s), 5.10(2H, s), 4.75(2H, s), 4.30(1H, m), 3.95(1H, m), 3.85(1H, m), 3.15 (1H, m), 3.10(2H, m), 1.28(2H, m), 1.09(2H, m) CDCl.sub.3 510 25 79 8 ##STR57## 8.60(1H, d), 8.57(1H, s), 8.52 (1H, d), 8.03(1H, d), 7.80(1H, d), 7.41(1H, q), 5.18(2H, s), 4.65(2H, s), 4.17(1H, m), 3.94 (1H, m), 3.75(1H, m), 3.30(2H, m), 3.04(1H, m), 2.81(1H, m), 2.73(1H, m), 1.30-1.00(4H, DMSO-d.sub.6 467 90 70 9 ##STR58## 8.82(1H, s), 8.05(1H, d), 7.51 (1H, d), 7.45(1H, m), 6.5(1H, s), 5.02(2H, m), 4.5(2H, m), 4.20(1H, m), 3.95(1H, m), 3.70 (1H, m), 3.00(1H, m), 2.80(1H, m), 2.70(1H, m), 1.00(4H, m) DMSO 456 15 69 10 ##STR59## 8.58(1H, s), 8.00(1H, d), 7.10 (3H, m), 6.72(1H, s), 4.80(2H, s), 4.20(1H, m), 3.95(1H, m), 3.85(1H, m), 3.10(1H, m), 2.95 (2H, m), 1.07(4H, m) DMSO 542 20 65 11 ##STR60## 8.76(1H, s), 8.20(1H, m), 8.02 (1H, d), 7.89(1H, m), 7.40(1H, m), 5.60(2H, s), 4.78(2H, m), 4.45(1H, m), 3.85(1H, m), 3.70 (1H, m), 3.10(2H, m), 1.30(2H, m), 1.15(2H. m) DMSO 541 25 73 __________________________________________________________________________
TABLE 9 __________________________________________________________________________ Examples 13 to 22 ##STR62## FAB, Reac. Examp. NMR MS time Yield No. R .sup.1 H NMR, δ (ppm) solv. (M + 1) (hr) (%) __________________________________________________________________________ 13 ##STR63## 8.6(1H, s), 7.8(1H, d), 7.2(3H, d), 6.9(2H, d), 5.1(2H, s), 4.4 (2H, s), 3.9(1H, m), 3.8(1H, m), 3.7(3H, s), 3.65(1H, m), 3.0 (1H, m), 2.9-2.7(2H, m), 1.3- 1.1(4H, DMSO-d.sub.6 495 2 60 14 ##STR64## 8.6(1H, s), 7.8(1H, d), 7.4(2H, d), 7.3(3H, m), 5.1(2H, s), 4.4 (2H, s), 3.9(1H, m), 3.8(1H, m), 3.7(1H, m), 3.0(1H, m), 2.9-2.7 (2H, m), 1.4(9H, s), 1.3-1.1 (4H, DMSO-d.sub.6 521 2 65 15 ##STR65## 8.6(1H, s), 7.8(1H, d), 7.4(2H, m), 7.2(3H, m), 5.1(2H, s), 4.4 (2H, s), 3.9(1H, m), 3.8(1H, m), 3.7(1H, m), 3.0(1H, m), 2.9-2.7 (2H, m), 1.3-1.1(4H, DMSO-d.sub.6 483 4 67 16 ##STR66## 8.6(1H, s), 8.2(2H, d), 7.8(1H, d), 7.6(2H, d). 7.2(1H, d), 5.3 (2H, s), 4.4(2H, s), 3.9(1H, m), 3.8(1H,m), 3.7(1H, m), 3.0(1H, m), 2.9-2.7(2H, m), 1.3-1.1 (4H, DMSO-d.sub.6 510 3 58 17 ##STR67## 8.6(1H, s), 7.9-7.4(5H, m), 7.2 (1H, d, ), 5.3(2H, s), 4.4(2H, s), 3.9(1H, m), 3.8(1H, m), 3.7(1H, m), 3.0(1H, m), 2.9-2.7(2H, m), 1.3-1.1(4H, m) DMSO-d.sub.6 490 4 55 18 ##STR68## 8.6(1H, s), 7.8(1H, d), 7.2(1H, d), 6.9(3H, m), 6.1(2H, s), 5.1 (2H, s), 4.4(2H, s), 3.9(1H, m), 3.8(1H, m), 3.7(1H, m), 3.0(1H, m), 2.9-2.7(2H, m), 1.3-1.1 (4H, DMSO-d.sub.6 509 4 71 19 ##STR69## 8.6(3H, m), 7.8(2H, m), 7.4(1H, q), 7.2(1H, d), 5.2(2H, s), 4.4 (1H, m), 3.9(1H, m), 3.8(1H, m), 3.7(1H, m), 3.0(1H, m), 2.9-2.7 (2H, m), 1.3-1.1(4H, DMSO-d.sub.6 466 4 53 20 ##STR70## 8.6(1H, s), 7.8(1H, d), 7.5(2H, m), 7.2(1H, d), 6.5(1H ,m), 5.0 (2H, m), 4.4(1H, m), 3.9(1H, m), 3.8(1H, m), 3.7(1H, m), 3.0(1H, m), 2.9-2.7(2H, m), 1.3-1.1 (4H, DMSO-d.sub.6 455 4 60 21 ##STR71## 8.6(1H, s), 7.8(1H, d), 7.2(1H, d), 7.1(3H, m), 6.7(1H, s), 4.4 (1H, m), 3.9(1H, m), 3.8(1H, m), 3.7(1H, m), 3.0(1H, m), 2.9-2.7 (2H, m), 1.3-1.1(4H, DMSO-d.sub.6 541 4 50 22 ##STR72## 8.6(1H, s), 8.2(1H, m), 7.9-7.8 (2H, m), 7.4(1H, m), 7.2(1H, d), 5.6(2H, s), 4.4(1H, m), 3.9(1H, m), 3.8(1H, m), 3.0(1H, m), 2.9- 2.7(2H, m), 1.3-1.1(4H, DMSO-d.sub.6 540 4 70 __________________________________________________________________________
TABLE 10 __________________________________________________________________________ Examples 24 to 33 ##STR74## FAB, Reac. Examp. NMR MS time Yield No. R .sup.1 H NMR, δ (ppm) solv. (M + 1) (hr) (%) __________________________________________________________________________ 24 ##STR75## 8.6(1H, s), 7.7(1H, d), 7.2(2H, d), 6.9(2H, d), 5.1(2H, s), 4.3 (2H, s), 4.1(1H, m), 3.9(1H, m), 3.8(1H, m), 3.7(3H, s), 2.9(1H, m), 2.8-2.7(2H, m), 1.15(4H, DMSO-d.sub.6 513 2 75 25 ##STR76## 8.6(1H, s), 7.7(1H, d), 7.5(2H, m), 7.1(2H, m), 5.1(2H, s), 4.3 (2H, s), 4.1(1H, m), 3.9(1H, m), 3.8(1H, m), 2.9(1H, m), 2.8-2.7 (2H, m), 1.4(9H, s), 1.15(4H, DMSO-d.sub.6 539 4 70 26 ##STR77## 8.6(1H, s), 7.7(1H, d), 7.3(2H, m), 7.1(2H, m), 5.1(2H, s), 4.3 (2H, s), 4.1(1H, m), 3.9(1H, m), 3.8(1H, m), 2.9(1H, m), 2.8-2.7 (2H, m), 1.15(4H, m) DMSO-d.sub.6 501 4 80 27 ##STR78## 8.6(1H, s), 8.2(2H, d), 7.7(1H, d), 7.6(2H, d), 5.3(2H, s), 4.3 (2H, s), 4.1(1H, m,), 3.9(1H, m), 3.8(1H, m), 2.9(1H, m), 2.8-2.7 (2H, m), 1.15(4H, m) DMSO-d.sub.6 528 3 68 28 ##STR79## 8.6(1H, s), 7.9-7.4(5H, m), 5.3 (2H, s), 4.3(2H, s), 4.1(1H, m), 3.9(1H, m), 3.8(1H, m), 2.9(1H, m), 2.8-2.7(2H, m), 1.15(4H, m) DMSO-d.sub.6 508 2 70 29 ##STR80## 8.6(1H, s), 7.7(1H, d), 7.0(3H, m), 6.1(2H, s), 5.1(2H, s), 4.3 (2H, s), 4.1(1H, m), 3.9(1H, m), 3.8(1H, m), 2.9(1H, m), 2.8-2.7 (2H, m), 1.15(4H, m) DMSO-d.sub.6 527 3 69 30 ##STR81## 8.6(3H, m), 7.8(1H, d), 7.7(1H, d), 7.4(1H, q), 5.3(2H, s), 4.3 (2H, s), 4.1(1H, m), 3.9(1H, m), 3.8(1H, m), 2.9(1H, m), 2.8-2.7 (2H, m), 1.15(4H, m) DMSO-d.sub.6 484 3 58 31 ##STR82## 8.6(1H, s), 7.7(1H, d), 7.5(2H, m), 6.5(1H, m), 5.0(2H, m), 4.3 (2H, s), 4.1(1H, m), 3.9(1H, m), 3.8(1H, m), 2.9(1H, m), 2.8-2.7 (2H, m), 1.15(4H, m) DMSO-d.sub.6 473 3 70 32 ##STR83## 8.6(1H, s), 7.7(1H, d), 7.1(3H, m), 6.6(1H, s), 4.3(2H, s), 4.1 (1H, m), 3.9(1H, m), 3.8(1H, m), 2.9(1H, m), 2.8-2.7(2H, m), 1.15(4H, m) DMSO-d.sub.6 559 4 59 33 ##STR84## 8.6(1H, s), 8.3(1H, m), 7.9(1H, m), 7.7(1H, d), 7.4(1H, m), 5.6 (2H, s), 4.3(2H, s), 4.1(1H, m), 3.9(1H, m), 3.8(1H, m), 2.9(1H, m), 2.8-2.7(2H, m), 1.15(4H, DMSO-d.sub.6 558 4 60 __________________________________________________________________________
TABLE 11 __________________________________________________________________________ Examples 35 to 44 ##STR86## FAB, Reac. Examp. NMR MS time Yield No. R .sup.1 H NMR, δ (ppm) solv. (M + 1) (hr) (%) __________________________________________________________________________ 35 ##STR87## 8.7(1H, s), 7.9(1H, d), 7.3(2H, d), 7.0(2H, d), 5.1(2H, s), 4.4 (2H, s), 4.3(1H, m), 3.8(1H, m), 3.7(3H, s), 3.0(1H, m), 2.9-2.6 (2H, s), 1.2-0.9(4H, DMSO-d.sub.6 529 3 63 36 ##STR88## 8.7(1H, s), 7.9(1H, d), 7.5(2H, d), 7.3(2H, d), 5.2(2H, s), 4.4 (2H, s), 4.3(1H, m), 3.8(1H, m), 3.0(1H, m), 2.9-2.7(2H, m), 1.4 (9H, s), 1.2-0.9(4H, DMSO-d.sub.6 555 3 73 37 ##STR89## 8.7(1H, s), 7.9(1H, d), 7.4(2H, m), 7.1(2H, m), 5.1(2H, s), 4.4 (2H, s), 4.3(1H, m), 3.8(1H, m), 3.0(1H, m), 2.9-2.7(2H, m), 1.2-0.9(4H, m) DMSO-d.sub.6 517 2 80 38 ##STR90## 8.7(1H, s), 8.3(2H, d), 7.9(1H, d), 7.7(2H, d), 5.4(2H, s), 4.4 (2H, s), 4.3(1H, m), 3.8(1H, m), 3.0(1H, m), 2.9-2.7(2H, m), 1.2-0.9(4H, m) DMSO-d.sub.6 544 4 63 39 ##STR91## 8.7(1H, s), 7.9-7.4(5H, m), 5.3 (2H, s), 4.4(2H, s), 4.3(1H, m), 3.8(1H, m), 3.0(1H, m), 2.9-2.7 (2H, m), 1.2-0.9(4H, m) DMSO-d.sub.6 524 4 70 40 ##STR92## 8.7(1H, s), 7.9(1H, d), 7.0(3H, m), 6.1(2H, s), 5.1(2H, s), 4.4 (2H, s), 4.3(1H, m), 3.8(1H, m), 3.0(1H, m), 2.9-2.7(2H, m), 1.2-0.9(4H, m) DMSO-d.sub.6 543 2 67 41 ##STR93## 8.7(1H, s), 7.9(1H, d), 8.6(2H, m), 7.8(1H, d), 7.4(1H, q), 5.2 (2H, s), 4.4(2H, s), 4.3(1H, m), 3.8(1H, m), 3.0(1H, m), 2.9-2.7 (2H, m), 1.2-0.9(4H, DMSO-d.sub.6 500 4 60 42 ##STR94## 8.7(1H, s), 7.9(1H, d), 7.5(2H, m), 6.5(1H, m), 5.0(2H, m), 4.4 (2H, s), 4.3(1H, m), 3.8(1H, m), 3.0(1H, m), 2.9-2.7(2H, m), 1.2-0.9(4H, m) DMSO-d.sub.6 489 2 62 43 ##STR95## 8.7(1H, s), 7.9(1H, d), 7.1(3H, m), 6.7(1H, s), 4.4(2H, s), 4.3 (1H, m), 3.8(1H, m), 3.0(1H, m), 2.9-2.6(2H, m), 1.2-0.9(4H, m) DMSO-d.sub.6 575 4 60 44 ##STR96## 8.7(1H, s), 8.2(1H, m), 7.9(2H, m), 7.4(1H, m), 5.6(2H, s), 4.4 (2H, s), 4.3(1H, m), 3.8(1H, m), 3.0(1H, m), 2.9-2.7(2H, m), 1.2-0.9(4H, m) DMSO-d.sub.6 574 4 76 __________________________________________________________________________
TABLE 12 __________________________________________________________________________ Examples 46 to 55 ##STR98## FAB, Reac. Examp. NMR MS time Yield No. R .sup.1 H NMR, δ (ppm) solv. (M + 1) (hr) (%) __________________________________________________________________________ 46 ##STR99## 8.8(1H, s), 7.8(1H, d), 7.4(2H, d), 7.1(2H, d), 5.2(2H, s), 4.6 (2H, s), 4.3(1H, m), 4.1(1H, m), 3.9(1H, m), 3.8(3H, s), 3.0(1H, m), 2.9-2.7(2H, m), 2.7(3H, s), 1.3(2H, m), 0.95(2H, m) DMSO-d.sub.6 525 17 38 47 ##STR100## 8.8(1H, s), 7.8(1H, d), 7.6(2H, d), 7.4(2H, d), 5.3(2H, s), 4.6 (2H, s), 4.3(1H, m), 4.1(1H, m), 3.9(1H, m), 3.0(1H, m), 2.9-2.7 (2H, m), 2.7(3H, s), 1.5(9H, s), 1.3(2H, m), 0.95(2H, m) DMSO-d.sub.6 551 17 34 48 ##STR101## 8.8(1H, s), 7.8(1H, d), 7.5(2H, m), 7.2(2H, m), 5.2(2H, s), 4.6 (2H, s), 4.3(1H, m), 4.1(1H, m), 3.9(1H, m), 3.0(1H, m), 2.9-2.7 (2H, m), 2.7(3H, s), 1.3(2H, m), 0.95(2H, m) DMSO-d.sub.6 513 17 40 49 ##STR102## 8.8(1H, s), 8.3(2H, d), 7.8(1H, d), 7.7(2H, d), 5.4(2H, s), 4.6 (2H, s), 4.3(1H, m), 4.1(1H, m), 3.9(1H, m), 3.0(1H, m), 2.9-2.7 (2H, m), 2.7(3H, s), 1.3(2H, m), 0.95(2H, m) DMSO-d.sub.6 540 17 37 50 ##STR103## 8.8(1H, s), 8.0-7.5(5H, m), 5.4 (2H, s), 4.6(2H, s), 4.3(1H, m), 4.1(1H, m), 3.9(1H, m), 3.0(1H, m), 2.9--2.7(2H, m), 2.7(3H, s), 1.3(2H, m), 0.95(2H, DMSO-d.sub.6 520 17 42 51 ##STR104## 8.8(1H, s), 7.8(1H, d), 7.0(3H, m), 6.2(2H, s), 5.2(2H, s), 4.6 (2H, s), 4.3(1H, m), 4.1(1H, m), 3.9(1H, m), 3.0(1H, m), 2.9-2.7 (2H, m), 2.7(3H, s), 1.3(2H, m), 0.95(2H, m) DMSO-d.sub.6 539 17 44 52 ##STR105## 8.8(1H, s), 8.6(2H, m), 7.9(1H, d), 7.8(1H, d), 7.4(1H, q), 5.3 (2H, s), 4.6(2H, s), 4.3(1H, m), 4.1(1H, m), 3.9(1H, m), 3.0(1H, m), 2.9-2.7(2H,m), 2.7(3H, s), 1.3(2H,m), 0.95(2H, m) DMSO-d.sub.6 496 17 30 53 ##STR106## 8.8(1H, s), 7.8(1H, d), 7.6(2H, m), 6.5(1H, m), 5.1(2H, m), 4.6 (2H, s), 4.3(1H, m), 4.1(1H, m), 3.9(1H, m), 3.0(1H, m), 2.9-2.7 (2H, m), 2.7(3H, s), 1.3(2H, m), 0.95(2H, m) DMSO-d.sub.6 485 17 29 54 ##STR107## 8.8(1H, s), 7.8(1H, d), 7.2(3H, m), 6.8(1H, s), 4.6(2H, s), 4.3 (1H, m), 4.1(1H, m), 3.9(1H, m), 3.0(1H, m), 2.9-2.7(2H, m), 2.7 (3H, s), 1.3(2H, m), 0.95(2H, DMSO-d.sub.6 571 20 27 55 ##STR108## 8.8(1H, s), 8.3(1H, m), 8.0(1H, m), 7.8(1H, d), 7.5(1H, m), 5.7 (2H, s), 4.6(2H, s), 4.3(1H, m), 4.1(1H, m), 3.9(1H, m), 3.0(1H, m), 2.9-2.7(2H, m), 2.7(3H, s), 1.3(2H, m), 0.95(2H, m) DMSO-d.sub.6 570 17 42 __________________________________________________________________________
TABLE 13 __________________________________________________________________________ Examples 57 to 66 ##STR110## FAB, Reac. Examp. NMR MS time Yield No. R .sup.1 H NMR, δ (ppm) solv. (M + 1) (hr) (%) __________________________________________________________________________ 57 ##STR111## 8.4(1H, s), 7.4(2H, bs), 7.2 (2H, d), 7.0(2H, d), 5.1(2H, s), 4.6(2H, m), 4.2(1H, m), 3.9(1H, m), 3.8(3H, s), 3.7(1H, m), 3.0 (1H, m), 2.8-2.6(2H, m), 1.1 (4H, DMSO-d.sub.6 528 10 59 58 ##STR112## 8.4(1H, s), 7.5(2H, d), 7.4(2H, bs), 7.3(2H, d), 5.2(2H, s), 4.6 (2H, m), 4.2(1H, m), 3.9(1H, m), 3.7(1H, m), 3.0(1H, m), 2.8-2.6 (2H, m), 1.4(9H, s), 1.1(4H, DMSO-d.sub.6 554 17 67 59 ##STR113## 8.4(1H, s), 7.4(4H, m), 7.1(2H, m), 5.1(2H, s), 4.6(2H, m), 4.2 (1H, m), 3.9(1H, m), 3.7(1H, m), 3.0(1H, m), 2.8-2.6(2H, m), 1.1 (4H, s) DMSO-d.sub.6 516 17 55 60 ##STR114## 8.4(1H, s), 8.2(2H, d), 7.6(2H, d), 7.4(2H, bs), 5.3(2H, s), 4.6 (2H, m), 4.2(1H, m), 3.9(1H, m), 3.7(1H, m), 3.0(1H, m), 2.8-2.6 (2H, m), 1.1(4H, s) DMSO-d.sub.6 543 17 56 61 ##STR115## 8.4(1H, s), 7.9-7.4(6H, m), 5.3 (2H, s), 4.6(2H, m), 4.2(1H, m), 3.9(1H, m), 3.7(1H, m), 3.0(1H, m), 2.8-2.6(2H, m), 1.1(4H, s) DMSO-d.sub.6 523 18 62 62 ##STR116## 8.4(1H, s), 7.3(2H, bs), 7.0 (3H, m), 6.2(2H, s), 5.2(2H, s), 4.6(2H, m), 4.2(1H, m), 3.9(1H, m), 3.7(1H, m), 3.0(1H, m), 2.8- 2.6(2H, m), 1.1(4H, s) DMSO-d.sub.6 542 18 65 63 ##STR117## 8.5(3H, m,), 7.6(1H, d), 7.4(1H, q), 7.3(2H, bs), 5.3(2H, s), 4.6 (2H, m), 4.2(1H, m), 3.9(1H, m), 3.7(1H, m), 3.0(1H, m), 2.8-2.6 (2H, m), 1.1(4H, s) DMSO-d.sub.6 499 17 52 64 ##STR118## 8.4(1H, s), 7.5-7.4(4H, m), 6.5 (1H, m), 5.0(2H, m), 4.6(2H, m), 4.2(1H, m), 3.9(1H, m), 3.7(1H, m), 3.0(1H, m), 2.8-2.6(2H, m), 1.1(4H, s) DMSO-d.sub.6 488 18 49 65 ##STR119## 8.4(1H, s), 7.4(2H, bs), 7.1 (3H, m), 6.7(1H, s), 4.6(2H, m), 4.2(1H, m), 3.9(1H, m), 3.7(1H, m), 3.0(1H, m), 2.8-2.6(2H), 1.1(4H, s) DMSO-d.sub.6 574 18 43 66 ##STR120## 8.4(1H, s), 8.2(1H, m), 7.9(1H, m), 7.4(3H, m), 5.6(2H, s), 4.6 (2H, m), 4.2(1H, m), 3.9(1H, m), 3.7(1H, m), 3.0(1H, m), 2.8-2.6 (2H, m), 1.1(4H, s) DMSO-d.sub.6 573 17 65 __________________________________________________________________________
TABLE 14 __________________________________________________________________________ Examples 68 to 77 ##STR122## FAB, Reac. Examp. NMR MS time Yield No. R .sup.1 H NMR, δ (ppm) solv. (M + 1) (min) (%) __________________________________________________________________________ 68 ##STR123## 8.9(1H, s), 8.1(1H, d), 7.8(1H, m), 7.6(1H, dd), 7.3(3H, m), 7.1 (2H, d), 5.2(2H, s), 4.3(2H, s), 4.0(1H, m), 3.9(1H, m), 3.8(3H, s), 3.0(1H, m), 2.8-2.6(2H, DMSO-d.sub.6 568 20 78 69 ##STR124## 8.9(1H, s), 8.1(1H, d), 7.8(1H, m), 7.6(2H, m), 7.3(2H, m), 5.2 (2H, s), 4.3(2H, s), 3.9(1H, m), 3.0(1H, m), 2.8-2.6(2H, m), 1.5 (9H, s) DMSO-d.sub.6 594 10 80 70 ##STR125## 8.9(1H, s), 8.1(1H, d), 7.8(1H, m), 7.6(1H, dd), 7.4(2H, m), 7.3 (1H, dd), 7.1(2H, m), 5.1(2H, s), 4.3(2H, s), 4.0(1H, m), 3.9 (1H, m), 3.0(1H, m), 2.8-2.6 (2H, DMSO-d.sub.6 556 15 81 71 ##STR126## 8.9(1H, s), 8.3(2H, d), 8.1(1H, d), 7.8(1H, m), 7.7(2H, d), 7.6 (1H, dd), 7.3(1H, m), 5.3(2H, s), 4.3(2H, s), 4.0(1H, m, 3.9 (1H, m), 3.0(1H, m), 2.8-2.6 (2H, DMSO-d.sub.6 583 15 75 72 ##STR127## 8.8(1H, s), 8.1(1H, d), 7.9-7.4 (6H, m), 7.3(1H, dd), 5.3(2H, s), 4.3(2H, s), 4.0(1H, m), 3.9 (1H, m), 3.0(1H, m), 2.8-2.6 (2H, m) DMSO-d.sub.6 563 15 80 73 ##STR128## 8.8(1H, s), 8.1(1H, d), 7.8(1H, m), 7.6(1H, dd), 7.3(1H, dd), 7.0(3H, m), 6.2(2H, s), 5.1(2H, s), 4.3(2H, s), 4.0(1H, m), 3.9 (1H, m), 3.0(1H, m), 2.8-2.6 (2H, DMSO-d.sub.6 582 15 87 74 ##STR129## 8.8(1H, s), 8.6(1H, s), 8.5(1H, q), 7.8(2H, m), 7.6(1H, dd), 7.4 (1H, q), 7.3(1H, dd), 5.2(2H, s), 4.3(2H, s), 4.0(1H, m), 3.9 (1H, m), 3.0(1H, m), 2.8-2.6 (2H, DMSO-d.sub.6 539 15 70 75 ##STR130## 8.8(1H, s), 8.1(1H, d), 7.8(1H, m), 7.6(1H, dd), 7.5(1H, d), 7.45(1H, dd), 6.6(1H, m), 5.0 (2H, m), 4.3(2H, s), 4.0(1H, m), 3.9(1H, m), 3.0(1H, m), 2.8-2.6(2H, DMSO-d.sub.6 528 10 69 76 ##STR131## 8.8(1H, s), 8.1(1H, d), 7.8(1H, m), 7.6(1H, dd), 7.3(1H, dd), 7.1(3H, m), 6.7(1H, s), 4.3(2H, s), 4.0(1H, m), 3.9(1H, m), 3.0 (1H, m), 2.8-2.6(2H, m) DMSO-d.sub.6 614 20 59 77 ##STR132## 8.8(1H, s), 8.2(1H, m), 8.1(1H, d), 8.0(1H, m), 7.8(1H, d), 7.6 (1H, dd), 7.4(1H, m), 7.3(1H, dd), 5.6(2H, s), 4.3(2H, s), 4.0 (1H, m), 3.9(1H, m), 3.0(1H, m), 2.8-2.6(2H, m,) DMSO-d.sub.6 613 10 82 __________________________________________________________________________
TABLE 15 __________________________________________________________________________ Examples 79 to 88 ##STR134## FAB, Reac. Examp. NMR MS time Yield No. R .sup.1 H NMR, δ (ppm) solv. (M + 1) (hr) (%) __________________________________________________________________________ 79 ##STR135## 8.8(1H, s), 7.8(1H, d), 7.4(2H, d), 7.1(2H, d), 5.0(2H, s), 4.5 (2H, q), 4.4(2H, s), 4.2(1H, m), 3.9(1H, m), 3.7(3H, s), 3.1(1H, m), 2.9-2.7(2H, m), 1.45(3H, DMSO-d.sub.6 501 4 73 80 ##STR136## 8.8(1H, s), 7.8(1H, d), 7.4(2H, d), 7.2(2H, d), 5.1(2H, s), 4.5 (2H, q), 4.4(2H, s), 4.1(1H, m), 3.9(1H, m), 3.1(1H, m), 2.9-2.7 (2H, m), 1.45(3H, t), 1.4(9H, DMSO-d.sub.6 527 2.5 77 81 ##STR137## 8.8(1H, s), 7.8(1H, d), 7.3(2H, m), 7.0(2H, m), 5.0(2H, s), 4.5 (2H, q), 4.4(2H, s), 4.2(1H, m), 3.9(1H, m), 3.1(1H, m), 2.9-2.7 (2H, m), 1.45(3H, t) DMSO-d.sub.6 489 3 80 82 ##STR138## 8.8(1H, s), 8.3(2H, d), 7.8(1H, d), 7.7(2H, d), 5.3(2H, s), 4.5 (2H, q), 4.4(2H, s), 4.2(1H, m), 3.9(1H, m), 3.1(1H, m), 2.9-2.7 (2H, m), 1.45(3H, t) DMSO-d.sub.6 516 3 75 83 ##STR139## 8.8(1H, s), 7.9-7.4(5H, m), 5.3 (2H, s), 4.5(2H, q), 4.4(2H, s), 4.2(1H, m), 3.9(1H, m), 3.1(1H, m), 2.9-2.7(2H, m), 1.45(3H, t) DMSO-d.sub.6 496 3 80 84 ##STR140## 8.8(1H, s), 7.8(1H, d), 6.8(3H, m), 6.0(2H, s), 5.0(2H, s), 4.5 (2H, q), 4.4(2H, s), 4.2(1H, m), 3.9(1H, m), 3.1(1H, m), 2.9-2.7 (2H, m), 1.45(3H, t) DMSO-d.sub.6 515 4 69 85 ##STR141## 8.8(1H, s), 8.6(2H, m), 7.8(2H, m), 7.4(1H, q), 5.3(2H, s), 4.5 (2H, q), 4.4(2H, s), 4.2(1H, m), 3.9(1H, m), 3.1(1H, m), 2.9-2.7 (2H, m), 1.45(3H, t) DMSO-d.sub.6 471 2 70 86 ##STR142## 8.8(1H, s), 7.8(1H, d), 7.5(2H, m), 6.5(1H, m), 5.0(2H, m), 4.5 (2H, q), 4.4(2H, s), 4.2(1H, m), 2.9(1H, m), 3.1(1H, m), 2.9-2.7 (2H, m), 1.45(3H, t) DMSO-d.sub.6 461 2 67 87 ##STR143## 8.8(1H, s), 7.8(1H, d), 7.1(3H, m), 6.7(1H, s), 4.5(2H, q), 4.4 (2H, s), 4.2(1H, m), 3.9(1H, m), 3.1(1H, m), 2.9-2.7(2H, m), 1.45(3H, t) DMSO-d.sub.6 547 3 63 88 ##STR144## 8.8(1H, s), 8.2(1H, m), 7.9(1H, m), 7.8(1H, d), 7.4(1H, m), 5.6 (2H, s), 4.5(2H, q), 4.4(2H, s), 4.2(1H, m), 3.9(1H, m), 3.1(1H, m), 2.9-2.7(2H, m), 1.5(3H, DMSO-d.sub.6 546 4 70 __________________________________________________________________________
TABLE 16 __________________________________________________________________________ Examples 97 to 106 ##STR153## FAB, Reac. Examp. NMR MS time Yield No. R .sup.1 H NMR, δ (ppm) solv. (M + 1) (min) (%) __________________________________________________________________________ 97 ##STR154## 8.6(1H, s), 8.0(1H, d), 4.7(1H, m), 4.6(2H, s), 4.2(1H, m), 3.9 (1H, m), 3.7(1H, m), 3.0(1H, m), 2.9-2.7(2H, m), 1.2-1.0(4H, m), 0.9(6H, d) DMSO-d.sub.6 418 10 73 98 ##STR155## 8.6(1H, s), 8.05(1H, d), 4.8 (1H, m), 4.7(2H, s), 4.2(1H, m), 4.0(1H, m), 3.7(1H, m), 3.0(1H, m), 2.9-2.7(2H, m), 2.2(2H, m), 2.1(2H, m), 1.7(1H, m), 1.5(1H, m), 1.2-1.0(4H, DMSO-d.sub.6 430 10 63 99 ##STR156## 8.6(1H, s), 8.0(1H, d), 4.7(1H, m), 4.5(2H, s), 4.2(1H, m), 3.9 (1H, m), 3.7(1H, m), 3.1(1H, m), 2.9-2.8(2H, m), 1.7(4H, s), 1.6 (2H, m), 1.5(2H, m), 1.2-1.0 (4H, m) DMSO-d.sub.6 444 50 77 100 ##STR157## 8.6(1H, s), 8.0(1H, d), 4.8(1H, m), 4.6(2H, s), 4.2(1H, m), 3.9 (1H, m), 3.8-3.6(5H, m), 3.1 (1H, m), 2.9-2.7(2H, m), 2.3- .9(2H, m), 1.2-1.0(4H, m) DMSO-d.sub.6 446 30 61 101 ##STR158## 8.65(1H, s), 8.05(1H, d), 4.6 (2H, s), 4.25(1H, m), 3.9(1H, m), 3.85(2H, dd), 3.75(1H, m), 3.1(1H, m), 3.0-2.8(2H, m), 1.3-1.0(5H, m), 0.5(2H, m), 0.3(2H, m) DMSO-d.sub.6 430 30 84 102 ##STR159## 8.6(1H, s), 8.0(1H, d), 4.6(2H, s), 4.2(1H, m), 3.95(1H, m), 3.8 (2H, d), 3.7(1H, m), 3.05(1H, m), 2.9-2.7(2H, m), 1.9(1H, m), 1.2-1.0(4H, m), 0.9(6H, d) DMSO-d.sub.6 432 15 80 103 ##STR160## 8.60(1H, s), 8.05(1H, d), 4.74 (2H, s), 4.60(2H, s), 4.21(1H, m), 3.97(1H, m), 3.75(1H, m), 3.50(1H, s), 3.35(2H, s), 3.08 (1H, m), 2.90-2.70(2H, m), 1.30-1.05(4H, m) DMSO-d.sub.6 414 90 63 104 ##STR161## 8.6(1H, s), 8.0(1H, d), 4.6(2H, s), 4.2(1H, m), 4.1(2H, t), 3.9 (1H, m), 3.7(1H, m), 3.1(1H, m), 2.9-2.7(2H, m), 2.8(1H, s), 2.5 (2H, t), 1.2-1.0(4H, m) DMSO-d.sub.6 428 15 65 105 ##STR162## 8.6(1H, s), 8.0(1H, d), 4.6(2H, s), 4.2(1H, m), 3.9(1H, m), 3.7 (1H, m), 3.4(2H, s), 3.3(3H, s), 3.0(1H, m), 2.8-2.6(2H, m), 1.2-1.0(4H, m) DMSO-d.sub.6 420 20 52 106 ##STR163## 8.6(1H, s), 8.05(1H, d), 4.6 (2H, s), 4.3(2H, t), 4.2(1H, m), 3.9(1H, m), 3.8(2H, t), 3.7(1H, m), 3.1(1H, m), 2.9-2.7(2H, m), 1.2-1.0(4H, m) DMSO-d.sub.6 438 10 50 __________________________________________________________________________
TABLE 17 __________________________________________________________________________ Examples 107 to 116 ##STR164## FAB, Reac. Examp. NMR MS time Yield No. R .sup.1 H NMR, δ (ppm) solv. (M + 1) (hr) (%) __________________________________________________________________________ 107 ##STR165## 8.8(1H, s), 7.8(1H, d), 4.7(1H, m), 4.5(2H, s), 4.1(1H, m), 3.9 (1H, m), 3.8(1H, m), 2.9(1H, m), 2.8-2.7(2H, m), 1.15(4H, s), 0.9(6H, d) DMSO-d.sub.6 435 2 69 108 ##STR166## 8.8(1H, s), 7.8(1H, d), 4.8(1H, m), 4.4(2H, s), 4.1(1H, m), 3.9 (1H, m), 3.8(1H, m), 2.9(1H, m), 2.8-2.7(2H, m), 2.2(2H, m), 2.1 (2H, m), 1.7(1H, m), 1.5(1H, m), 1.15(4H, DMSO-d.sub.6 447 2 61 109 ##STR167## 8.8(1H, s), 7.8(1H, d), 4.7(1H, m), 4.5(2H, s), 4.1(1H, m), 3.9 (1H, m), 3.8(1H, m), 2.9(1H, m), 2.8-2.7(2H, m), 1.7(4H, s), 1.6 (2H, m), 1.5(2H, m), 1.15(2H, m), 1.0(2H, DMSO-d.sub.6 461 2 63 110 ##STR168## 8.8(1H, s), 7.8(1H, d), 4.8(1H, m), 4.5(2H, s), 4.1(1H, m), 3.9 (1H, m), 3.8-3.6(4H, m), 3.1 (1H, m), 2.8-2.7(2H, m), 2.3- .9(2H, m), 1.2-1.0(4H, s) DMSO-d.sub.6 463 2 54 111 ##STR169## 8.8(1H, s), 7.8(1H, d), 4.5 (2H, s), 4.1(1H, m), 3.9(1H, m), 3.8(2H, dd), 3.75(1H, m), 3.1 (1H, m), 2.8-2.7(2H, m), 1.15 (4H, m), 1.05(1H, m), 0.5(2H, m), 0.3(2H, m) DMSO-d.sub.6 447 2 59 112 ##STR170## 8.8(1H, s), 7.8(1H, d), 4.5(2H, s), 4.1(1H, m), 3.9(1H, m), 3.8 (2H, d), 3.75(1H, m), 3.0(1H, m), 2.8-2.7(2H, m), 1.9(1H, m), 1.2-1.0(4H, m), 0.9(6H, d) DMSO-d.sub.6 449 2 64 113 ##STR171## 8.8(1H, s), 7.8(1H, d), 4.62 (2H, s), 4.3(2H, s), 4.1(1H, m), 3.9(1H, m), 3.8(1H, m), 3.5 (1H, s), 2.9(1H, m), 2.8-2.7 (2H, m), 1.15(4H, m) DMSO-d.sub.6 431 4 55 114 ##STR172## 8.8(1H, s), 7.8(1H, d), 4.5(2H, s), 4.1(1H, m), 4.0(2H, t), 3.9 (1H, m), 3.8(1H, m), 3.1(1H, m), 2.8-2.7(2H, m), 2.7(1H, s), 2.5 (2H, t), 1.2(4H, m) DMSO-d.sub.6 445 2 65 115 ##STR173## 8.8(1H, s), 7.8(1H, d), 4.5(2H, s), 4.1(1H, m), 3.9(1H, m), 3.8 (1H, m), 3.3(2H, s), 3.1(3H, s), 3.0(1H, m), 2.8-2.7(2H, m), 1.15(4H, m) DMSO-d.sub.6 437 1.5 47 116 ##STR174## 8.8(1H, s), 7.8(1H, d), 4.5(2H, s), 4.3(2H, t), 4.1(1H, m), 3.9 (1H, m), 3.8(2H, t), 3.75(1H, m), 3.0(1H, m), 2.8-2.7(2H, m), 1.15(4H, m) DMSO-d.sub.6 455 1.5 53 __________________________________________________________________________
TABLE 18 __________________________________________________________________________ Examples 117 to 126 ##STR175## FAB, Reac. Examp. NMR MS time Yield No. R .sup.1 H NMR, δ (ppm) solv. (M + 1) (hr) (%) __________________________________________________________________________ 117 ##STR176## 8.8(1H, s), 7.9(1H, d), 4.7(1H, m), 4.4(2H, s), 4.3(1H, m), 3.8 (1H, m), 3.7(1H, m), 3.0(1H, m), 2.9-2.7(2H, m), 1.8-0.9(4H, m), 0.9(6H, d) DMSO-d.sub.6 451 2.5 68 118 ##STR177## 8.8(1H, s), 7.9(1H, d), 4.7(1H, m), 4.4(2H, s), 4.3(1H, m), 3.8 (1H, m), 3.7(1H, m,), 3.0(1H, m), 2.9-2.7(2H, m), 2.2(2H, m), 2.1(2H, m), 1.7(1H, m), 1.5(1H, m), 1.12-0.9(4H, DMSO-d.sub.6 463 2 61 119 ##STR178## 8.8(1H, s), 7.9(1H, d), 4.7(1H, m), 4.4(2H, s), 4.3(1H, m), 3.8 (1H, m), 3.7(1H, m), 3.0(1H, m), 2.9-2.7(2H, m), 1.7(4H, s), 1.6 (2H, m), 1.5(2H, m), 1.2-0.9 (4H, m) DMSO-d.sub.6 477 2 55 120 ##STR179## 8.8(1H, s), 7.9(1H, d), 4.8(1H, m), 4.4(2H, s), 4.3(1H, m), 3.8- 3.6(6H, m), 3.0(1H, m), 2.9-2.7 (2H, m), 2.3-1.9(2H, m), 1.2- 0.9(4H, m) DMSO-d.sub.6 479 2.5 49 121 ##STR180## 8.8(1H, s), 7.9(1H, d), 4.4 (2H, s), 4.3(1H, m), 3.8-3.7 (4H, m), 3.0(1H, m), 2.9-2.7 (2H, m), 1.2-0.9(5H, m), 0.5 (2H, m), 0.3(2H, m) DMSO-d.sub.6 463 2 52 122 ##STR181## 8.8(1H, s), 7.9(1H, d), 4.4(2H, s), 4.3(1H, m), 3.8-3.7(4H, m), 3.0(1H, m), 2.9-2.7(2H, m), 1.9(1H, m), 1.2-0.9(4H, m), 0.9(6H, d) DMSO-d.sub.6 465 2 60 123 ##STR182## 8.8(1H, s), 7.9(1H, d), 4.61 (2H, s), 4.4(2H, s), 4.3(1H, m), 3.8(1H, m), 3.5(1H, s), 3.0(1H, m), 2.9-2.7(2H, m), 1.2-0.9(4H, m) DMSO-d.sub.6 447 2 62 124 ##STR183## 8.8(1H, s), 7.9(1H, d), 4.4(2H, s), 4.3(1H, m), 4.1(2H, t), 3.8 (1H, m), 3.7(1H, m), 3.0(1H, m), 2.9-2.7(2H, m), 2.8(1H, s), 2.5 (2H, t), 1.2-0.9(4H, m) DMSO-d.sub.6 461 2.5 57 125 ##STR184## 8.8(1H, s), 7.9(1H, d), 4.4(2H, s), 4.3(1H, m), 3.8(1H, m), 3.7 (1H, m), 3.3(2H, s), 3.1(3H, s), 3.0(1H, m), 2.9-2.7(2H, m), 1.2-0.9(4H, m) DMSO-d.sub.6 453 1.5 51 126 ##STR185## 8.8(1H, s), 7.9(1H, d), 4.4(2H, s), 4.3(3H, m), 3.8-3.7(4H, m), 3.0(1H, m), 2.9-2.7(2H, m), 1.2-0.9(4H, m) DMSO-d.sub.6 471 2 64 __________________________________________________________________________
TABLE 19 __________________________________________________________________________ Examples 127 to 136 ##STR186## FAB, Reac. Examp. NMR MS time Yield No. R .sup.1 H NMR, δ (ppm) solv. (M + 1) (hr) (%) __________________________________________________________________________ 127 ##STR187## 8.6(1H, s), 7.8(1H, d), 7.2(1H, d), 4.6(1H, m), 4.4(2H, s), 3.9 (1H, m), 3.8(1H, m), 3.7(1H, m), 3.0(1H, m), 2.9-2.7(2H, m), 1.3-1.1(4H, m), 0.9(6H, d) DMSO-d.sub.6 417 3 55 128 ##STR188## 8.6(1H, s), 7.8(1H, d), 7.2 (1H, d), 4.7(1H, m), 4.4(2H, s), 3.9(1H, m), 3.8(1H, m), 3.0(1H, m), 2.9-2.7(2H, m), 2.2(2H, m), 2.1(2H, m), 1.7(1H, m), 1.5(2H, m), 1.3-1.1(4H, DMSO-d.sub.6 429 3 52 129 ##STR189## 8.6(1H, s), 7.8(1H, d), 7.2(1H, d), 4.7(1H, m), 4.4(2H, s), 3.9 (1H, m), 3.8(1H , m), 3.7(1H, m), 3.0(1H, m), 2.9-2.7(2H, m), 1.7 (4H, s), 1.6(2H, m), 1.5(2H, m), 1.3-1.1(4H, DMSO-d.sub.6 443 3 59 130 ##STR190## 8.6(1H, s), 7.8(1H, d), 7.2(1H, d), 4.8(1H, m), 4.4(2H, s), 3.9 (1H, m), 3.8-3.6(6H, m), 3.0 (1H, m), 2.9-2.7(2H, m), 2.3- .9(2H, m), 1.3-1.1(4H, m) DMSO-d.sub.6 445 3 45 131 ##STR191## 8.6(1H, s), 7.8(1H, d), 7.2(1H, d), 4.6(1H, m), 4.4(2H, s), 3.9 (1H, m), 3.8-3.7(3H, m), 3.1 (1H, m), 2.9-2.7(2H, m), 1.3- .1(4H, m), 1.0(1H, m), 0.5(2H, m), 0.3(2H, m) DMSO-d.sub.6 429 3 57 132 ##STR192## 8.6(1H, s), 7.8(1H, d), 7.2(1H, d), 4.4(2H, s), 3.9(1H, m), 3.8 (3H, m), 3.7(1H, m), 3.1(1H, m), 2.9-2.7(2H, m), 1.9(1H, m), 1.3-1.1(4H, m), 0.9(6H, d) DMSO-d.sub.6 431 3 76 133 ##STR193## 8.6(1H, s), 7.8(1H, d), 7.2(1H, d), 4.6(2H, s), 4.4(2H, s), 3.9 (1H, m), 3.8(1H, m), 3.7(1H, m), 3.5(1H, s), 3.0(1H, m), 2.9- 2.7(2H, m), 1.3-1.1(4H, m) DMSO-d.sub.6 413 3 49 134 ##STR194## 8.6(1H, s), 7.8(1H, d), 7.2(1H, d), 4.4(2H, s), 4.1(2H, t), 3.9 (1H, m), 3.8(1H, m), 3.7(1H, m), 3.1(1H, m), 2.9-2.7(2H, m), 2.8(1H, s), 2.5(2H, t), 1.3- 1.1(4H, m) DMSO-d.sub.6 427 3 59 135 ##STR195## 8.6(1H, s), 7.8(1H, d), 7.2(1H, d), 4.4(2H, s), 4.1(2H, t), 3.9 (1H, m), 3.8(1H, m), 3.7(1H, m), 3.3(2H, s), 3.2(3H, s), 3.0(1H, m), 2.9-2.7(2H, m), 1.3-1.1 (4H, m) DMSO-d.sub.6 419 1.5 47 136 ##STR196## 8.6(1H, s), 7.8(1H, d), 7.2(1H, d), 4.4(2H, s), 4.3(2H, t), 3.9 (1H, m), 3.8(3H, m), 3.7(1H, m), 3.0(1H, m), 2.9-2.7(2H, m), 1.3-1.1(4H, m) DMSO-d.sub.6 437 2 53 __________________________________________________________________________
TABLE 20 __________________________________________________________________________ Examples 137 to 146 ##STR197## FAB, Reac. Examp. NMR MS time Yield No. R .sup.1 H NMR, δ (ppm) solv. (M + 1) (hr) (%) __________________________________________________________________________ 137 ##STR198## 8.8(1H, s), 7.8(1H, d), 4.7(1H, m), 4.5(2H, s), 4.3(1H, m), 4.1 (1H, m), 3.9(1H, m), 3.0(1H, m), 2.8-2.7(2H, m), 2.65(3H, s), 1.3(2H, m), 1.0(2H, m), 0.9 (6H, d) DMSO-d.sub.6 447 9 57 138 ##STR199## 8.8(1H, s), 7.8(1H, d), 4.8(1H, m), 4.7(2H, s), 4.3(1H, m), 4.2 (1H, m), 3.9(1H, m), 3.0(1H, m), 2.9-2.7(2H, m), 2.7(3H, s), 2.2 (2H, m), 2.1(2H, m), 1.6(1H, m), 1.5(1H, m), 1.3(2H, m), 0.95 (2H, m) DMSO-d.sub.6 459 12 65 139 ##STR200## 8.8(1H, s), 7.8(1H, d), 4.7(1H, m), 4.5(2H, s), 4.3(1H, m), 4.2 (1H, m), 3.9(1H, m), 3.1(1H, m), 2.9-2.8(2H, m), 2.7(3H, s), 1.7 (4H, s), 1.6(2H, m), 1.5(2H, m), 1.3(2H, m), 0.9(2H, m) DMSO-d.sub.6 473 12 63 140 ##STR201## 8.8(1H, s), 7.8(1H, d), 4.8(1H, m), 4.6(2H, s), 4.3(1H, m), 4.2 (1H, m), 4.0(1H, m), 3.8-3.6 (4H, m), 3.1(1H, m), 2.9-2.7 (2H, m), 2.7(3H, s), 2.3-1.9 (2H, m), 1.3(2H, m), 0.9(2H, DMSO-d.sub.6 475 12 42 141 ##STR202## 8.8(1H, s), 7.8(1H, d), 4.6 (2H, s), 4.3(1H, m), 3.9(1H, m), 3.85(2H, dd), 3.1(1H, m), 3.0- 2.8(2H, m), 2.7(3H, s), 1.3(2H, ), 1.1(1H, m), 0.9(2H, m), 0.5(2H, m), 0.3(2H, DMSO-d.sub.6 459 12 63 142 ##STR203## 8.8(1H, s), 7.8(1H, d), 4.6(2H, s), 4.3(1H, m), 4.2(1H, m), 3.95 (1H, m), 3.8(2H, d), 3.05(1H, m), 2.9-2.7(2H, m), 2.7(3H, s), 1.9(1H, m), 1.3(2H, m), 1.0(2H, m), 0.9(6H, DMSO-d.sub.6 461 12 68 143 ##STR204## 8.8(1H, s), 7.8(1H, d), 4.62 (2H, s), 4.60(2H, s), 4.3(1H, m), 4.1(1H, m), 3.9(1H, m), 3.5 (1H, s), 3.0(1H, m), 2.7(3H, s), 2.9-2.7(2H, m), 1.3(2H, m), 1.0(2H, m) DMSO-d.sub.6 443 12 30 144 ##STR205## 8.8(1H, s), 7.8(1H, d), 4.6(2H, s), 4.3(1H, m), 4.2(1H, m), 4.15(2H, t), 3.1(1H, m), 2.9- 2.7(2H, m), 2.8(1H, s), 2.7(3H, s), 2.5(3H, t), 1.3(2H, m), 0.9(2H, m) DMSO-d.sub.6 457 12 52 145 ##STR206## 8.8(1H, s), 7.8(1H, d), 4.6(2H, s), 4.3(1H, m), 4.15(1H, m), 3.9 (1H, m), 3.3(2H, s), 3.1(3H, s), 2.9(1H, m), 2.8-2.6(2H, m), 2.7(3H, s), 1.3(2H, m), 0.9(2H, m) DMSO-d.sub.6 449 8 39 146 ##STR207## 8.8(1H, s), 7.8(1H, d), 4.6(2H, s), 4.3(2H, t), 4.25(1H, m), 4.2 (1H, m), 3.9(1H, m), 3.8(2H, t), 2.9-2.7(2H, m), 2.7(3H, s), 1.3 (2H, m), 1.0(2H, m) DMSO-d.sub.6 467 12 57 __________________________________________________________________________
TABE 21 __________________________________________________________________________ Examples 147 to 156 ##STR208## FAB, Reac. Examp. NMR MS time Yield No. R .sup.1 H NMR, δ (ppm) solv. (M + 1) (hr) (%) __________________________________________________________________________ 147 ##STR209## 8.4(1H, s), 7.7(2H, br), 4.5 (1H, m), 4.3(2H, s), 4.0-3.8 (3H, m), 3.2(1H, m), 2.8-2.6 (2H, m), 1.1(4H, s), 0.9 (6H, DMSO-d.sub.6 450 5 73 148 ##STR210## 8.3(1H, s), 7.3(2H, br), 4.8 (1H, m), 4.3(2H, s), 4.0-3.8 (3H, m), 2.8-2.6(2H, m), 2.2 (2H, m), 2.1(2H, m), 1.6(1H, m), 1.5(1H, m), 1.1(4H, m) DMSO-d.sub.6 462 8 64 149 ##STR211## 8.4(1H, s), 7.4(2H, br), 4.7 (1H, m), 4.5(2H, s), 4.2(1H, m), 3.9(1H, m), 3.7(1H, m), 3.0(1H, m), 2.8-2.6(2H, m), 1.7(4H, s), 1.6(2H, m), 1.5(2H, m), 1.1 (4H, m) DMSO-d.sub.6 476 8 61 150 ##STR212## 8.4(1H, s), 7.4(2H, br), 4.8 (1H, m), 4.6(2H, s), 4.2(1H, m), 4.0(1H, m), 3.8-3.6(4H, m), 3.0(1H, m), 2.8-2.6(2H, m), 2.3-1.9(2H, m), 1.2-0.9(4H, m) DMSO-d.sub.6 478 12 54 151 ##STR213## 8.4(1H, s), 7.5(2H, br), 4.6 (2H, s), 3.9(1H, m), 3.8(2H, dd), 3.0(1H, m), 2.9-2.8(2H, m), 1.0(1H, m), 0.5(2H, m), 0.3(2H, DMSO-d.sub.6 462 5 82 152 ##STR214## 8.4(1H, s), 7.5(2H, br), 4.5 (2H, s), 3.9(1H, m), 3.8(2H, dd), 3.1(1H, m), 2.9-2.7(2H, m), 1.9(1H, m), 1.2-1.1(4H, m), 0.9(6H, d) DMSO-d.sub.6 464 6 75 153 ##STR215## 8.4(1H, s), 7.4(2H, br), 4.6 (2H, s), 4.59(2H, m), 4.2(1H, m), 3.9(1H, m), 3.7(1H, m), 3.5 (1H, s), 3.0(1H, m), 2.8-2.6 (2H, m), 1.1(4H, s) DMSO-d.sub.6 446 4 50 154 ##STR216## 8.4(1H, s), 7.5(2H, br), 4.4 (2H, s), 4.1(1H, m), 4.0(2H, t), 3.9(1H, m), 3.8(1H, m), 3.1(1H, m), 2.8-2.7(2H, m), 2.8(1H, s), 2.5(2H, t), 1.2-0.9(4H, m) DMSO-d.sub.6 460 5 70 155 ##STR217## 8.4(1H, s), 7.4(2H, br), 4.4 (2H, s), 4.3(2H, t), 4.1(1H, m), 3.9(1H, m), 3.7(2H, t), 3.6(1H, m), 3.3(2H, s), 3.0(3H, s), 2.9 (1H, m), 2.8-2.6(2H, m), 1.3-0.9(4H, m) DMSO-d.sub.6 452 3 60 156 ##STR218## 8.4(1H, s), 7.4(2H, br), 4.4 (2H, s), 4.3(2H, t), 4.0(2H, m), 3.9(1H, m), 3.8(2H, t), 3.7(1H, m), 3.2(1H, m), 2.9-2.7(2H, m), 1.1(4H, s) DMSO-d.sub.6 470 5 72 __________________________________________________________________________
TABLE 22 __________________________________________________________________________ Examples 157 to 166 ##STR219## FAB, Reac. Examp. NMR MS time Yield No. R .sup.1 H NMR, δ (ppm) solv. (M + 1) (min) (%) __________________________________________________________________________ 157 ##STR220## 8.8(1H, s), 8.1(1H, d), 7.8(1H, m), 7.6(1H, dd), 7.3(1H, dd), 4.6(1H, m), 4.3(2H, s), 4.0(1H, m), 3.9(1H, m), 3.0(1H, m), 2.8-2.6(2H, m), 0.9(6H, d) DMSO-d.sub.6 490 15 64 158 ##STR221## 8.8(1H, s), 8.1(1H, d), 7.8(1H, m), 7.6(1H, dd), 7.3(1H, dd), 4.7(1H, m), 4.4(2H, s), 4.0(1H, m), 3.9(1H, m), 3.0(1H, m), 2.8- 2.6(2H, m), 2.2(2H, m), 2.1(2H, m), 1.7(1H, m), 1.5(1H, m) DMSO-d.sub.6 502 20 61 159 ##STR222## 8.8(1H, s), 8.1(1H, d), 7.8(1H, m), 7.6(1H, dd), 7.3(1H, dd), 4.7(1H, m), 4.4(2H, s), 4.0(1H, m), 3.9(1H, m), 3.0(1H, m), 2.8- 2.6(2H, m), 2.2(2H, m), 2.1(2H, m), 1.7(1H, m), 1.5(1H, m) DMSO-d.sub.6 516 35 70 160 ##STR223## 8.8(1H, s), 8.1(1H, d), 7.8(1H, m), 7.6(1H, dd), 7.3(1H, dd), 4.8(1H, m), 4.4(2H, s), 4.0(1H, m), 3.9(1H, m), 3.8-3.6(4H, m), 3.0(1H, m), 2.9-2.6(2H, m), 2.3-1.9(2H, m) DMSO-d.sub.6 518 35 55 161 ##STR224## 8.8(1H, s), 8.1(1H, d), 7.8 (1H, dd), 7.6(1H, dd), 7.3(1H, dd), 4.6(2H, s), 4.2(1H, m), 3.9(1H, m), 3.8(2H, dd), 3.0 (1H, m), 2.8-2.6(2H, m), 1.1 (1H, m), 0.5(2H, m), 0.3(2H, DMSO-d.sub.6 502 30 65 162 ##STR225## 8.8(1H, s), 8.1(1H, d), 7.8(1H, dd), 7.6(1H, dd), 7.3(1H, dd), .6(2H, s), 4.0(1H, m), 3.9(1H, m), 3.8(2H, d), 3.0(1H, m), 2.8-2.6(2H, m), 1.9(1H, m), 0.9(6H, d) DMSO-d.sub.6 504 20 70 163 ##STR226## 8.79(1H, s), 8.01(1H, d), 7.8 (1H, m), 7.6(1H, dd), 7.3(1H, dd), 4.73(2H, s), 4.61(2H, s), 4.21(1H, m), 3.75(1H, m), 3.50 (1H, s), 3.35(2H, s), 3.08(1H, m), 2.90-2.70(2H, DMSO-d.sub.6 486 60 52 164 ##STR227## 8.8(1H, s), 8.1(1H, d), 7.8(1H, m), 7.6(1H, dd), 7.3(1H, dd), 4.6(2H, s), 4.1(1H, m), 4.0(2H, t), 3.9(1H, m), 3.0(1H, m), 2.8-2.6(2H, m), 2.7(1H, s), 2.5(2H, t) DMSO-d.sub.6 500 25 53 165 ##STR228## 8.8(1H, s), 8.1(1H, d), 7.8(1H, m), 7.6(1H, dd), 7.3(1H, dd), 4.6(2H, s), 4.1(1H, m), 3.9(1H, m), 3.3(2H, s), 3.1(3H, s), 3.0 (1H, m), 2.8-2.6(2H, m) DMSO-d.sub.6 492 30 47 166 ##STR229## 8.8(1H, s), 8.1(1H, d), 7.8(1H, m), 7.6(1H, dd), 7.3(1H, m), 4.6 (2H, s), 4.3(2H, t), 4.1(1H, m), 3.9(1H, m), 3.8(2H, t), 3.1(1H, m), 2.8-2.6(2H, m) DMSO-d.sub.6 510 15 51 __________________________________________________________________________
TABLE 23 __________________________________________________________________________ Examples 167 to 176 ##STR230## FAB, Reac. Examp. NMR MS time Yield No. R .sup.1 H NMR, δ (ppm) solv. (M + 1) (hr) (%) __________________________________________________________________________ 167 ##STR231## 8.8(1H, s), 7.8(1H, d), 4.6(1H, m), 4.5(2H, q), 4.4(2H, s), 4.2 (1H, m), 3.9(1H, m), 3.1(1H, m), 2.9-2.7(2H, m), 1.45(3H, t), 0.9(6H, d) DMSO-d.sub.6 423 4.5 82 168 ##STR232## 8.8(1H, s), 7.8(1H, d), 4.7(1H, m), 4.5(2H, q), 4.4(2H, s), 4.2 (1H, m), 4.1(1H, m), 3.1(1H, m), 2.9-2.7(2H, m), 2.2(2H, m), 2.1 (2H, m), 1.7(1H, m), 1.6(1H, m), 1.45(3H, DMSO-d.sub.6 435 5 73 169 ##STR233## 8.8(1H, s), 7.8(1H, d), 4.75 (1H, m), 4.6(2H, s), 4.5(2H, q), 4.2(1H, m), 3.9(1H, m), 3.0-2.7 (2H, m), 1.8(4H, s), 1.65(2H, s), 1.5(2H, s), 1.4(3H, t) DMSO-d.sub.6 449 5 77 170 ##STR234## 8.7(1H, s), 7.8(1H, d), 4.8(1H, m), 4.55(2H, s), 4.5(2H, dd), 4.15(1H, m), 3.85(1H, m), 3.7 (2H, m), 3.1(1H, m), 2.9-2.7 (2H, m), 2.1-1.9(2H, m), 1.5 (3H, t) DMSO-d.sub.6 451 6 71 171 ##STR235## 8.8(1H, s), 7.8(1H, d), 4.6 (2H, s), 4.45(2H, m), 4.25(1H, m), 3.9(2H, dd), 3.7(1H, m), 3.1(1H, m), 1.45(3H, t), 0.5 (2H, m), 0.25(2H, m) DMSO-d.sub.6 435 5 84 172 ##STR236## 8.8(1H, s), 7.8(1H, d), 4.6(2H, s), 4.5(2H, q), 4.2(1H, m), 3.9 (1H, m), 3.85(2H, dd), 3.1(1H, m), 2.9-2.7(2H, m), 1.9(1H, m), 0.9(6H, d) DMSO-d.sub.6 437 4 70 173 ##STR237## 8.8(1H, s), 7.8(1H, d), 4.62 (2H, s), 4.5(2H, q), 4.4(2H, s), 4.2(1H, m), 3.9(1H, m), 3.5(1H, s), 3.1(1H, m), 2.9-2.7(2H, m), 1.45(3H, t) DMSO-d.sub.6 419 3 50 174 ##STR238## 8.8(1H, s), 7.8(1H, d), 4.5(2H, dd), 4.2(1H, m), 4.15(2H, t), 3.9(1H, m), 3.1(1H, m), 2.9- 2.7(2H, m), 2.8(1H, s), 2.5(2H, t), 1.5(3H, t) DMSO-d.sub.6 433 4.5 72 175 ##STR239## 8.8(1H, s), 7.8(1H, d), 4.6(2H, s), 4.5(2H, dd), 4.15(1H, m), 3.9(1H, m), 3.3(2H, s), 3.1(3H, s), 2.9(1H, m), 2.8(1H, m), 2.6 (1H, m), 1.5(3H, t) DMSO-d.sub.6 425 2 39 176 ##STR240## 8.8(1H, s), 7.8(1H, d), 4.6(2H, s), 4.5(2H, dd), 4.3(2H, t), 4.2 (1H, m), 3.9(1H, m), 3.8(2H, t), 2.9-2.7(2H, m), 1.5(3H, t) DMSO-d.sub.6 443 2 57 __________________________________________________________________________
TABLE 24 __________________________________________________________________________ Examples 183 to 202 ##STR247## FAB MS Reac. Ex. .sup.1 H NMR (DMSO-d.sub.6) (POS) Time Yield No. Q R.sub.1 R.sub.2 δ (ppm) M + H! (hr) (%) __________________________________________________________________________ 183 CF ##STR248## H 8.8(1H, s), 7.9(1H, d), 4.35(1H, m), 3.8(2H, m), 3.7(2H, m), 3.4 (1H, m), 3.0(2H, m), 1.2-1.0 (4H, 393 2.5 41 184 CF ##STR249## Et 8.8(1H, s), 7.9(1H, d), 4.4(1H, m), 4.2(2H, q), 4.1-3.9(2H, m), 3.4(2H, m), 2.8(2H, m), 1.4(3H, t), 1.25-1.0(4H, m) 421 2 38 185 CF ##STR250## Ph 8.8(1H, s), 7.9(1H, d), 7.3-7.1 (5H, m), 4.3(1H, m), 3.9-3.7(3H, m), 3.4(2H, m), 2.8(2H, m), 1.2 (2H, d), 1.05(2H, s) 469 4 29 186 CF ##STR251## tBu 8.8(1H, s), 7.9(1H, d), 4.35(1H, d), 4.1-3.9(3H, m), 3.4(2H, m), 2.9-2.7(2H, m), 1.35(9H, s), 1.2-0.95(4H, m) 449 2 35 187 CCl ##STR252## H 8.9(1H, s), 7.9(1H, d), 4.4(1H, m), 3.8(2H, m), 3.7(2H, m), 3.4 (1H, m), 2.9(2H, m), 1.25(2H, m), 1.1(2H, 409 1.5 39 188 CCl ##STR253## Et 8.9(1H, s), 7.9(1H, d), 4.35 (1H, m), 4.2(2H, q), 3.95-3.75 (3H, m), 3.7(2H, m), 3.4(2H, m), 2.85-2.7(2H, m), 1.4(3H, t), 1.3-1.15(4H, m) 437 1.5 37 189 CCl ##STR254## Ph 8.9(1H, s), 7.9(1H, d), 7.3-7.1 (5H, m), 4.35(1H, m), 4.1-3.9 (3H, m), 3.65(2H, m), 3.35(2H, m), 2.8-2.7(2H, m), 1.15(2H, d), 0.95(2H, s) 485 4.5 25 190 CCl ##STR255## tBu 8.9(1H, s), 7.85(1H, d), 4.3(1H, m),3.95-3.8(3H, m), 3.7(2H, m), 3.4(2H, m), 2.8(2H, m), 1.3(9H, s), 1.2-1.0(4H, m) 465 3 51 191 CH ##STR256## H 8.6(1H, s), 7.85(1H, d), 7.2(1H, d), 4.4(1H, m), 3.9(2H, m), 3.8- 3.65(3H, m), 2.9-2.7(2H, m), 1.3 (2H, d), 1.1(2H, s) 375 2.2 42 192 CH ##STR257## Et 8.6(1H, s), 7.8(1H, d), 7.2(1H, d), 4.4(1H, m), 4.25(2H, q), 3.9- 3.7(3H, m), 3.5(2H, m), 2.9-2.7 (2H, m), 1.3(3H, t), 1.25-0.95 (4H, m) 403 1.5 40 193 CH ##STR258## Ph 8.6(1H, s), 7.8(1H, d), 7.5-7.2 (5H, m, 1H, d), 4.35(1H, m), 4.0- 3.8(3H, m), 3.5(2H, m), 2.85-2.7 (2H, m), 1.3(2H, d), 1.15(2H, s) 451 4.5 31 194 CH ##STR259## tBu 8.6(1H, s), 7.75(1H, d), 7.2(1H, d), 4.35(1H, m), 4.0-3.8(3H, m), 3.5(2H, m), 2.9-2.7(2H, m), 1.4 (9H, s), 1.2-1.05(4H, m) 431 3 43 195 N ##STR260## H 8.6(1H, s), 8.1(1H, d), 4.5(2H, s), 4.3(1H, m), 3.8(1H, m), 3.65 (1H, m), 3.35(1H, m), 3.0-2.9 (2H, m), 1.2-1.0(4H, m) 376 1 61 196 N ##STR261## Et 8.6(1H, s), 8.05(1H, d), 4.55 (2H, s), 4.3(1H, m), 4.25(2H, q), 3.8(1H, m), 3.7(1H, m), 3.4 (1H, m), 3.0-2.85(2H, m), 1.35 (3H, t), 1.2-0.95(4H, 404 1 57 197 N ##STR262## Ph 8.6(1H, s), 8.1(1H, d), 7.7-7.3 (5H, m), 4.6(2H, s), 4.35(1H, m), 3.9(1H, m), 3.75(1H, m), 3.4(1H, m), 3.05-2.8(3H, m), 1.25(2H, d), 1.05(2H, 452 1 40 198 N ##STR263## tBu 8.6(1H, s), 8.05(1H, d), 4.55 (2H, s), 4.35(1H, m), 3.95(1H, m), 3.7(1H, m), 3.35(1H, m), 3.0- 2.85(2H, m), 1.35(9H, s), 1.15 (2H, d), 1.0(2H, s) 432 1.5 54 199 N ##STR264## H 8.85(1H, s), 8.1(1H, d), 7.75 (1H, m), 7.6(1H, dd), 7.35(1H, dd), 4.3(1H, m), 3.8(3H, m), 3.6 (1H, m), 3.0(1H, m), 2.7(2H, m) 448 1 33 200 N ##STR265## Et 8.85(1H, s), 8.05(1H, d), 7.75 (1H, m), 7.6(1H, dd), 7.35(1H, dd), 4.3(1H, m), 4.25(2H, q), 3.75(3H, m), 3.6(2H, m), 2.95 (2H, m), 2.7-2.6(2H, m), 1.4 (3H, 476 1 37 201 N ##STR266## Ph 8.85(1H, s), 8.1(1H, d), 7.75 (1H, m), 7.6(1H, dd), 7.55-7.35 (5H, m, 1H, dd), 4.35(1H, m), 3.75 (3H, m), 3.65(2H, m), 3.0(2H, m), 2.85(2H, m) 524 1.5 29 202 N ##STR267## tBu 8.85(1H, s), 8.05(1H, d), 7.75 (1H, m), 7.55(1H, dd), 7.3(1H, dd), 4.3(1H, m), 3.8(3H, m), 3.55 (2H, m), 2.9(2H, m), 2.7-2.65 (2H, m), 1.3(9H, 504 0.5 41 __________________________________________________________________________
TABLE 25 ______________________________________ Minimum Inhibitory Concentration of the test compounds (μg/ml) ______________________________________ Examples Test Strains 1 12 34 56 89 ______________________________________ Staphylococcus aureus ≦0.008 ≦0.008 ≦0.008 ≦0.008 ≦0.008 6538p Staphylococcus aureus ≦0.008 ≦0.008 ≦0.008 ≦0.008 ≦0.008 giorgio Staphylococcus aureus ≦0.008 ≦0.008 ≦0.008 ≦0.008 ≦0.008 77 Staphylococcus aureus 2 1 4 2 1 241 Staphylococcus ≦0.008 ≦0.008 ≦0.008 ≦0.008 ≦0.008 epidermidis 887E Staphylococcus 2 0.5 2 2 0.5 epidermidis 178 Streptococcus faecalis 0.031 0.031 0.13 0.016 0.063 29212 Bacillus subtilis 6633 ≦0.008 ≦0.008 ≦0.008 ≦0.008 ≦0.008 Micrococcus luteus 9341 0.063 0.13 0.13 0.063 0.25 Escherichia coli 10536 ≦0.008 ≦0.008 0.016 ≦0.008 0.016 Escherichia coli 3190Y ≦0.008 0.016 ≦0.008 ≦0.008 0.016 Escherichia coli 851E 0.016 0.063 0.13 ≦0.008 0.063 Escherichia coli 0.25 0.5 1 0.5 0.25 TEM3 3455E Escherichia coli 0.063 0.25 0.5 0.25 0.13 TEM5 3739E Escherichia coli 0.063 0.25 0.13 0.063 0.063 TEM9 2639E Pseudomonas aeruginosa 1 2 0.5 2 2 1912E Pseudomonas aeruginosa 2 0.5 2 2 2 10145 Acinetobacter ≦0.008 0.016 0.031 ≦0.008 0.031 calcoaceticus 15473 Citrobacter diversus 0.063 0.13 0.25 0.016 0.13 2046E Enterobacter cloacae 0.031 0.13 0.25 0.031 0.13 1194E Enterobacter cloacae ≦0.008 0.063 0.063 ≦0.008 0.016 P99 Klebsiella aerogenes 0.25 1 0.5 0.5 0.5 1976E Klebsiella aerogenes 0.063 0.13 0.031 0.016 0.25 1082E Salmonella typimurium 0.13 0.25 0.063 0.031 0.13 14028 ______________________________________ Examples Test Strains 97 102 103 104 177 ______________________________________ Staphylococcus aureus ≦0.008 0.016 ≦0.008 ≦0.008 ≦0.008 6538p Staphylococcus aureus ≦0.008 ≦0.008 ≦0.008 ≦0.008 ≦0.008 giorgio Staphylococcus aureus 0.016 0.016 ≦0.008 ≦0.008 0.016 77 Staphylococcus aureus 2 4 4 8 0.5 241 Staphylococcus ≦0.008 ≦0.008 ≦0.008 0.016 ≦0.008 epidermidis 887E Staphylococcus 1 1 4 4 1 epidermidis 178 Streptococcus faecalis 0.063 0.063 0.031 0.031 0.031 29212 Bacillus subtilis 6633 ≦0.008 ≦0.008 ≦0.008 ≦0.008 ≦0.008 Micrococcus luteus 9341 0.063 0.063 0.13 0.13 0.063 Escherichia coli 10536 ≦0.008 ≦0.008 ≦0.008 ≦0.008 ≦0.008 Escherichia coli 3190Y ≦0.008 ≦0.008 ≦0.008 ≦0.008 ≦0.008 Escherichia coli 851E 0.031 0.063 ≦0.008 ≦0.008 0.031 Escherichia coli 0.13 0.5 0.13 0.25 0.25 TEM3 3455E Escherichia coli 0.063 0.25 0.063 0.13 0.13 TEM5 3739E Escherichia coli 0.031 0.063 0.031 0.031 0.063 TEM9 2639E Pseudomonas aeruginosa 1 2 0.5 1 0.5 1912E Pseudomonas aeruginosa 1 2 0.5 1 0.5 10145 Acinetobacter 0.016 0.063 0.031 ≦0.008 0.13 calcoaceticus 15473 Citrobacter diversus 0.063 0.13 0.13 ≦0.008 0.031 2046E Enterobacter cloacae 0.063 0.25 0.016 ≦0.008 0.063 1194E Enterobacter cloacae ≦0.008 0.031 ≦0.008 0.016 0.016 P99 Klebsiella aerogenes 0.25 0.5 0.063 0.13 0.13 1976E Klebsiella aerogenes 0.13 0.25 0.031 0.031 0.063 1082E Salmonella typimurium 0.13 0.25 0.031 0.031 0.063 14028 ______________________________________ Examples Test Strains 178 179 180 OFLX CFLX ______________________________________ Staphylococcus aureus 0.031 ≦0.008 ≦0.008 0.25 0.13 6538p Staphylococcus aureus 0.016 0.016 ≦0.008 0.25 0.25 giorgio Staphylococcus aureus 0.031 0.031 ≦0.008 0.25 0.25 77 Staphylococcus aureus 1 2 2 64 64 241 Staphylococcus 0.031 0.016 ≦0.008 0.25 0.13 epidermidis 887E Staphylococcus 1 2 2 32 128 epidermidis 178 Streptococcus faecalis 0.063 0.031 0.063 2 0.5 29212 Bacillus subtilis 6633 0.016 ≦0.008 ≦0.008 0.063 0.031 Micrococcus luteus 9341 0.25 0.13 0.13 2 2 Escherichia coli 10536 0.031 <0.008 ≦0.008 0.031 ≦0.008 Escherichia coli 3190Y 0.016 ≦0.008 ≦0.008 0.016 ≦0.008 Escherichia coli 851E 0.063 ≦0.008 ≦0.008 0.063 0.016 Escherichia coli 1 0.13 0.25 0.5 0.25 TEM3 3455E Escherichia coli 0.5 0.063 0.13 0.5 0.13 TEM5 3739E Escherichia coli 0.25 0.031 0.031 0.063 0.031 TEM9 2639E Pseudomonas aeruginosa 0.5 0.25 0.25 0.5 0.31 1912E Pseudomonas aeruginosa 1 0.25 0.25 2 0.25 10145 Acinetobacter 0.13 0.016 0.0634 0.25 0.25 calcoaceticus 15473 Citrobacter diversus 0.13 0.031 0.016 0.063 0.016 2046E Enterobacter cloacae 0.13 0.031 0.031 0.063 0.031 1194E Enterobacter cloacae 0.063 0.008 ≦0.008 ≦0.008 ≦0.008 P99 Klebsiella aerogenes 0.5 0.13 0.13 0.25 0.13 1976E Klebsiella aerogenes 0.25 0.031 0.016 0.063 ≦0.008 1082E Salmonella typimurium 0.063 0.063 0.031 0.13 0.031 14028 ______________________________________ Note) OFLX = Ofloxacin CFLX = Ciprofloxacin
TABLE 26 ______________________________________ Pharmacokinetic parameters T.sub.1/2 C.sub.max T.sub.max F Route (hr) (μg/ml) (hr) (%) ______________________________________ CFLX IV 1.76 ± 0.035 71 PO 1.7 ± 0.108 1.34 ± 0.368 1.13 ± 0.605 EX. 89 IV 2.29 ± 1.13 >100 PO 6.69 ± 2.78 4.89 ± 2.23 2.18 ± 0.77 EX. 177 IV 1.92 ± 0.38 47.23 PO 3.93 ± 1.31 0.37 ± 0.11 0.51 ± 0.33 ______________________________________ Note: CFLX = Ciprofloxacin IV = Intravenous PO = Per oral T.sub.1/2 = Biological half life C.sub.max = Maximum blood concentration T.sub.max = Time showing maximum blood concentration after administration of the test compound F = Bioavailability
TABLE 27 ______________________________________ Toxicity Test Compound LD.sub.50 value (Example No.) (mg/kg) ______________________________________ 1 >3,000 34 >3,000 ______________________________________
TABLE 28 ______________________________________ Saturated salt solutions inside the desiccator Salt Solution Relative Humidity (%) at 25° C. ______________________________________Potassium Acetate 23Magnesium Chloride 33Potassium Carbonate 43Magnesium Nitrate 52Sodium Nitrite 64Sodium Chloride 75 ______________________________________
TABLE 29 ______________________________________ Thermal stability with elapsed time (at 70° C.) (Unit: %) Time (week)Sample Initial 1 2 3 4 ______________________________________ Anhydrate 99 -- 97 -- 95 3 hydrate 97 -- -- -- 94 1.5hydrate 100 97.25 95.80 97.16 96.17 ______________________________________
TABLE 30 ______________________________________ Water Solubility Phosphate buffered Phosphate buffered Sample solution (pH 7) solution (pH 2) ______________________________________ Free form 0.007 14.6 Tartarate 6.7 15.4 Sulfurate 11.4 8.9 p-Toluenesulfonate 7.5 6.8 Methanesulfonate >30 >20 ______________________________________
TABLE 31 ______________________________________ In vitro Antibacterial activity (Minimum Inhibitory Concentration: MIC, μg/ml) Test Strains E-isomer Z-isomer Ciprofloxacin ______________________________________ Staphylococcus aureus 6538p 0.063 ≦0.008 0.13 Staphylococcus aureus giorgio 0.063 ≦0.008 0.13 Staphylococcus aureus 77 0.063 0.031 0.25 Staphylococcus aureus 241 16 4 64 Staphylococcus epidermidis 0.031 ≦0.008 0.063 887E Staphylococcus epidermidis 178 32 4 128 Streptococcus faecalis 29212 0.25 0.063 1 Bacillus subtilis 6633 0.031 ≦0.008 0.031 Micrococcus luteus 9341 0.5 0.13 2 Escherichia coli 10536 0.031 ≦0.008 0.016 Escherichia coli 3190Y 0.016 ≦0.008 ≦0.008 Escherichia coli 851E 0.063 0.016 ≦0.008 Escherichia coli TEM3 3455E 0.5 0.13 0.25 Escherichia coli TEM5 3739E 0.5 0.13 0.13 Escherichia coli TEM9 2639E 0.13 0.031 0.016Pseudomonas aeruginosa 1912E 1 0.5 0.25 Pseudomonas aeruginosa 10145 2 0.5 0.25 Pseudomonas aeruginosa 6065Y 32 8 4 Acinetobacter calcoaceticus 0.25 0.063 0.25 15473 Citrobacter diversus 2046E 0.13 0.031 0.031 Enterobacter cloacae 1194E 0.13 0.031 0.016 Enterobacter cloacae P99 0.031 ≦0.008 ≦0.008 Klebsiella aerogenes 1976E 0.25 0.063 0.13 Klebsiella aerogenes 1082E 0.13 0.031 0.016 Proteus vulgaris 6059 1 0.25 0.031 Seratis marsecence 1826E 0.5 0.25 0.063 Salmonella thypimurium 14028 0.13 0.031 0.031 ______________________________________
TABLE 32 ______________________________________ In vitro Antibacterial activity (Minimum Inhibitory Concentration: MIC, μg/ml) Methanesulfonic Test Strains acid salt Ciprofloxacin ______________________________________ Staphylococcus aureus 6538p 0.016 0.13 Staphylococcus aureus giorgio 0.016 0.13 Staphylococcus aureus 77 0.031 0.25 Staphylococcus aureus 241 4 128 Staphylococcus epidermidis 887E 0.016 0.013 Staphylococcus epidermidis 178 4 128 Streptococcus faecalis 29212 0.13 0.5 Bacillus subtilis 6633 0.016 0.031 Micrococcus luteus 9341 0.13 2 Escherichia coli 10536 0.008 <0.008 Escherichia coli 3190Y 0.008 <0.008 Escherichia coli 851E 0.016 <0.008 Escherichia coli TEM3 3455E 0.25 0.5 Escherichia coli TEM5 3739E 0.13 0.13 Escherichia coli TEM9 2639E 0.031 0.016 Pseudomonas aeruginosa 1912E 0.25 0.13 Pseudomonas aeruginosa 10145 0.5 0.5 Acinetobacter calcoaceticus 15473 0.031 0.25 Citrobacter diversus 2046E 0.031 0.016 Enterobacter cloacae 1194E 0.031 0.016 Enterobacter cloacae P99 0.016 <0.008 Klebsiella aerogenes 1976E 0.13 0.13 Klebsiella aerogenes 1082E 0.031 0.016 Proteus vulgaris 6059 0.25 0.031 Seratis marsecence 1826E 0.13 0.063 Salmonella thypimurium 14028 0.031 0.031 ______________________________________
Claims (16)
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US08/825,992 US5776944A (en) | 1994-06-16 | 1997-04-04 | 7-(4-aminomethyl-3-methyloxyiminopyrroplidin-1-yl)-1-cyclopropyl-6-flu oro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid and the process for the preparation thereof |
US09/049,024 US5869670A (en) | 1994-06-16 | 1998-03-27 | 7-(4-aminomethyl-3-methyloxyiminopyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid and the process for the preparation thereof |
US09/188,063 US5962468A (en) | 1994-06-16 | 1998-11-09 | 7-(4-aminomethyl-3-methyloxyiminopyrrolidin-1-yl)-1- cyclopropyl-6-fluoro-4-oxo-1, 4-dihydro-1, 8-naphthyridine-3-carboxylic acid and the process for the preparation thereof |
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KR94-13604 | 1994-06-16 | ||
KR1019940013604A KR0131999B1 (en) | 1994-06-16 | 1994-06-16 | Novel quinoline carboxylic acid derivatives having 7-(4-aminomethyl-3-oxime) pyrrolidine substituent and process for preparing thereof novel substituted imidazole derivatives |
KR94-39930 | 1994-12-30 | ||
KR1019940039915A KR100222082B1 (en) | 1994-12-30 | 1994-12-30 | Novel quinoline carboxylic acid derivatives with 7-(3-aminomethyl-4-alkyloxime) pyrrolidine substituent and process for preparation thereof |
KR1019940039930A KR100222083B1 (en) | 1994-12-30 | 1994-12-30 | Novel quinoline carboxylic acid derivatives having (3-aminomethyl-4-benzyloxime)pyrrolidine substituient at 7 position and process for preparation thereof |
KR94-39915 | 1994-12-30 | ||
US08/490,978 US5633262A (en) | 1994-06-16 | 1995-06-15 | Quinoline carboxylic acid derivatives having 7-(4-amino-methyl-3-oxime) pyrrolidine substituent and processes for preparing thereof |
US08/825,992 US5776944A (en) | 1994-06-16 | 1997-04-04 | 7-(4-aminomethyl-3-methyloxyiminopyrroplidin-1-yl)-1-cyclopropyl-6-flu oro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid and the process for the preparation thereof |
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